6-azido-21-oxygenated-steroids of the pregnane series,methods for their manufacture and intermediates produced thereby

ABSTRACT

6-AZIDO-21-OXYGENATED-4-PREGNENE-3,20-DIONES AND THE 1-DEHYDRO-, 6-DEHYDRO-, AND 1,6-BIS-DEHYDRO-ANALOGS THEREOF POSSESS CORTICOID PROPERTIES. PREFERRED ARE THE 6DEHYDRO ANALOGS, I.E. THE 6-AZIDO-21-OXYGENATED-4,6PREGNADIENE-3,20-DIONES, HAVING ENHANCED ANTI-INFLAMMATORY ACTIVITY. COMPOUNDS USEFUL AS INTERMEDIATES WHICH ALSO POSSESS GLUCOCORTICOID PROPERTIES ARE 6B-AZIDO-7AHYDROXY-21-OXYGENATED-4-PREGNENE-3,20-DIONES AND THE 7A-ACYLATES THEREOF. THE PREFERRED 6-AZIDO-21-OXYGENATED-4,6-PREGNADIENE3,20-DIONES ARE PREPARED BY TREATING A 6A,7A-OXIDO-4PREGNENE WITH AN ALKALI METAL AZIDE IN AN AQUEOUS, INERT ORGANIC SOLVENT; ESTERIFYING THE THEREBY FORMED 6B-AZIDO7A-HYDROXY-4-PREGNENE; AND TREATING THE RESULTING 6BAZIDO-7A-ACYLOXY-4-PREGNENE WITH A TETRAALKYLAMMONIUM HALIDE IN AN APROTIC SOLVENT. ALTERNATIVELY, THE 6-AZIDO4,6-PREGNADIENES ARE PREPARED BY TREATING A 6B-AZIDO-7AHYDROXY-4-PREGNENE OR 7A-ACYLATE THEREOF WITH CONCENTRATED HYDROCHLORIC ACID IN A LOWER ALKANOIC ACID IN AN INERT SOLVENT. THE 6A-AZIDO-21-OXYGENATED-4-PREGNENE-3,20-DIONES AND 1-DEHYDRO ANALOGS THEREOF ARE PREPARED BY TREATING A 6BHALOGENO-(OR 6B-SULFONYLOXY)-21-OXYGENATED-4-PREGNENE3,20-DIONE OR 1-DEHYDRO-ANALOG THEREOF WITH AN ALKALI METAL AZIDE IN AN INERT SOLVENT. THE 6-AZIDO-21-OXYGENATED - 1,4,6 - PREGNATRIENE-3,20DIONES ARE PREPARED BY TREATING A T-AZIDO-21-OXYGENATED4,6-PREGNADIENE-3,20-DIONE WITH 2,3-DICHLORO-5,6-DICYANOBENZOQUINONE IN THE PRESENCE OF A STRONG ACID AND WATER.

United States Patent 3,784,603 6-AZIDO-21-OXYGENATED-STEROIDS OF THE PREGNANE SERIES, METHODS FOR THEIR MANUFACTURE AND INTERMEDIATES PRO- DUCED 'IHEREBY Elliot L. Shapiro, Cedar Grove, NJ., George J. Teutsch, Nancy, France, and Hershel L. Herzog, Glen Ridge, 11:15., assignors to Schering Corporation, Bloomfield, No Drawing. Continuation of abandoned application Ser. No. 59,367, July 29, 1970. This application July 13, 1972, Ser. No. 271,463

Int. Cl. C07c 173/10 US. Cl. 260-349 44 Claims ABSTRACT OF THE DISCLOSURE halide in an aprotic solvent. Alternatively, the 6-azido-- 4,6-pregnadienes are prepared by treating a 6B-azido-7uhydroxy-4-pregnene or 7m-acylate thereof with concentrated hydrochloric acid in a lower alkanoic acid in an inert solvent.

The 6a-azido-21-oxygenated-4-pregnene-3,ZO-diones and l-dehydro analogs thereof are prepared by treating a 6B- halogeno- (or 6fl-sulfonyloxy)-21-oxygenated-4-pregnene- 3,20-dione or l-dehydro-analog thereof with an alkali metal azide in an inert solvent.

The 6-azido-2l-oxygenated 1,4,6 pregnatriene-3,20- diones are prepared by treating a 6-azido-21-oxygenated- 4,6-pregnadiene-3,20-dione with 2,3-dichloro-5,6-dicyanobenzoquinone in the presence of a strong acid and water.

This is a continuation of application Ser. No. 59,367, filed July 29, 1970, now abandoned.

FIELD OF INVENTION This invention relates to novel compositions of matter and to processes for their preparation.

More specifically, this invention relates to compositions of matter which may be classified as 6-azido-3,20-diket0- 21-oxygenated-4'dehydro-steroids of the pregnane series, to methods for their manufacture, and to intermediates produced thereby.

SUMMARY OF INVENTION The invention sought to be patented in one compositionof-matter aspect resides in the concept of a chemical compound having a molecular structure comprising a steroid with a 21-oxygenated-4-pregnene-3,20-dione nucleus and having an azido group at 0-6, said steroids possessing corticoid properties. Those 6-azido-21-oxygenated-4- ice pregnene-3,20-diones of the composition-of-matter aspect of our invention which are also substituted at 0-11 by a halogen or an oxygenated function, and at 0-17 by an oxygenated function, possess glucocorticoid properties and are valuable as anti-inflammatory agents, a preferred species of this group being 6-azido-4,6-pregnadiene derivatives, particularly 6-azido-11,17,21-tri-oxygenated-4,6- pregnadiene-3,20-diones which have enhanced anti-inflammatory activity. Compounds of this composition-ofmatter aspect which are valuable mainly as intermediates are 21-hydrocarbonsulfonate esters of 6-azido-4,6-pregnadiene-21-ol-3,20-diones which are useful in the preparation of the corresponding pharmaceutically valuable 21- phosphate esters.

The invention sought to be patented in another composition-of-matter aspect resides in the concept of a chemical compound having a molecular structure comprising a steroid with a 2l-oxygenated-4-pregnene-3,20- dione nucleus and having an azido group at C-6 and a hydroxyl group or ester thereof at C-7, some of which compounds are valuable mainly as intermediates in preparing the preferred 6-azido-21-oxygenated-4,6-pregnadiene-3,20-diones of the aforementioned pharmacologically active composition-of-matter aspect of our invention. These compounds, particularly the 11-substituted-6fiazido-7a-hydroxy-4-pregnenes and their 7-lower alkanoate esters also possess glucocorticoid activity per se.

The invention sought to be patented in one process aspect resides in the concept of a method for preparing the preferred pharmacologically active 6-azido-21-oxygenated-4,6-pregnadiene-3,20 diones of our invention which comprises treating a 60;,7a-0Xid0-21-oxygenated-4-pregnene-3,20-dione with an alkali metal azide (preferably sodium azide) in an aqueous, inert organic solvent, esterifying the thereby formed 6fl-azido-7a-hydr0xy-21- oxygenated-4-pregnene-3,2J0-dione, and treating the resulting 6fl-azido-7u-acyloxy-21-oxygenated-4-pregnene-3, 20'dione with a tetraalkylammonium halide (preferably tetramethylammonium fluoride) in an aprotic solvent whereby is formed a 6-azido-21-oxygenated-4,6-pregnadiene-3,20-dione of our invention.

The invention sought to be patented in another process aspect provides another method for preparing the preferred 6-azido-2l-oxygenated-4,6-pregnadienes of our invention and resides in the concept of treating a member selected from the group consisting of a 6B-azido-7a-hydroxy-Zl-oxygenated-4-pregnene-3,20-dione and the 7:2- acyloxy derivatives thereof with concentrated hydro chloric acid in a lower alkanoic acid (preferably acetic acid) in an inert solvent, e.g. acetone or dioxane, whereby is formed a 6-azido-21-oxygenated-4,6-pregnadiene- 3,20-dione of our invention.

The invention sought to be patented in yet another process aspect resides in the concept of a method for preparing the pharmacologically active 6a-azido-21-oxygenated-4-pregnene-3,20-diones and the l-dehydro analogs thereof which comprises treating a member of the group consisting of a 6fl-L-21-oxygenated4-pregnene-3,20-dione and a 6fi-L-21-oxygenated-1,4-pregnadiene-3,20-dione said 6B-L- being a member selected from the group consisting of 6,8-chloro, oB-bromo, and GB-hydrocarbonsulfonyloxy having up to seven carbon atoms with an alkali metal azide (preferably sodium azide) in an inert organic solvent whereby is formed a 6a-azido-21-oxygenated-4- pregnene-3,20-dione of our invention.

GENERAL DESCRIPTION OF THE 6 AZIDO 4- PREGNENE COMPOSITION-OF-MATIER ASPECT OF THE INVENTION Included among the physical embodiments of one composition-of-matter aspect of our invention are novel compounds selected from the group consisting of 6-azido-21- oxygenated-4-pregnene-3,20-diones of following Formula I and the 1-dehydro-, 6-dehydro-, and 1,6-bis-dehydroanalogs thereof:

wherein Q is a member selected from the group consisting of hydrogen, hydroxy, and OR, R being an acyl radical of a hydrocarbon carboxylic acid having up to 12 carbon atoms;

W is a member selected from the group consisting of hydrogen (H,a-alkyl), (H,,8-alkyl), (I-La-OH), (H,aOR') wherein R is an acyl radical of a hydrocarbon carboxylic acid having up to 12 carbon atoms, =CHT where T is a member selected from the group consisting of hydrogen, alkyl, fluorine and chlorine, and W taken together with Q when Q is hydroxy and W is (I'LwhYdIOXY), the 160:, Hot-alkylidene derivatives thereof;

X is a member selected from the group consisting of hydrogen and halogen having an atomic weight less than 100;

Y is a member selected from the group consisting of hydrogen, oxygen, (H,;9OH), and, provided X is halogen, (H, 3 halogen of atomic weight less than 100);

Z is a member selected from the group consisting of hydroxy and OR" wherein R is an acyl radical of an acid selected from the group consisting of a hydrocarbon carboxylic acid having up to 12 carbon atoms, phosphoric acid and the monoand di-alkali metal and alkaline earth metal salts thereof, and Z taken together with Q when both Q and Z are hydroxy, the 17a,21-alkylidene derivatives thereof.

The alkyl groups included within the definition of the substituents W and T are preferably lower alkyl groups, i.e. radicals having usually up to four carbon atoms such as methyl, ethyl, n-propyl, iso-propyl, sec-butyl, and tert.- butyl, although higher homologs such as pentyl and hexyl come within the scope of this invention.

The alkylidene groups contemplated in the compounds of our invention are preferably lower alkylidenes, i.e. hydrocarbon radicals having preferably up to four carbon atoms and having a terminal double bond, including radicals such as methylene, ethylidene, n-propylidene, isopropylidene, n-butylidene, sec.-butylidene and tert.-butylidene and the like. The 16-lower alkylidene derivatives of this invention (i.e. when W in above Formula I is =CHT) are double bonded to the D-ring at C-16. The 16a,17u-alkylidenedioxy derivatives and the 17a,2l-alky1idenedioxy derivatives have the alkylidene terminal bonds attached to different oxygen atoms, i.e. to the oxygens at 0-16 and 0-17 in the case of the 16a,17a-alkylidenedioxy derivatives, or to the oxygens at (3-17 and C-21 in the case of the 17a,21-alkylidenedioxy derivatives.

As used in the specification and claims of this application, the term acyl denotes an organic radical derived from an organic acid by the removal of the hydroxyl group, e.g. acetyl is the acyl radical of acetic acid, benzenesulfonyl is the acyl radical of benzenesulfonic acid, and benzoyl is the acyl radical of benzoic acid.

The acyl radicals of the compounds of this invention as defined by Formula I hereinabove include those derived from hydrocarbon carboxylic acids having up to 12 carbon atoms which may be saturated, unsaturated, straight chain or branched chain, aliphatic, cyclic, cyclicaliphatic, aromatic, aryl-aliphatic, or alkyl-aromatic, and may be substituted by hydroxy, alkoxy containing from 1 to 5 carbon atoms or by halogen such as fluorine, chlorine, or bromine. Typical ester groups of the 6-azido-21-oxygenated-4-pregnene-3,20-diones of our invention are thus derived from hydrocarbon carboxylic acids such as alkanoic acids exemplified by formic, acetic, propionic, trimethylacetic, butyric, iso-butyric, tert.-butyric, valeric, isovaleric, caproic, caprylic, capric, undecylic and lauric acids; substituted alkanoic acids such as phenoxyacetic, trifluoroacetic, and fl-chloropropionic acids; aromatic and substituted aromatic acids including benzoic, toluic, p-chlorobenzoic acids; arylalkanoic acids such as phenylacetic and phenylpropionic acids; unsaturated acids such as acrylic and sorbic acids; and dibasic acids such as succinic, tartaric and phthalic acids.

Also contemplated as included within the acyl radicals defined by R, R and R" in compounds of structural Formula I hereinabove, are those derived from phosphoric acids and the monoand dialkali metal (e.g. sodium, potassium, lithium and alkaline earth metal salts (e.g. magnesium, calcium, barium) thereof.

The halogens at C-9 as defined by X in above Formula I are bromine, chlorine, and preferably fluorine.

The physical embodiment of the 6a-azido-4-pregnenes of Formula I, the 1-dehydro-, 6-dehydroand the 1,6-bisdehydro analogs thereof are characterized by being crystalline solids, usually off white to tan in color, which are insoluble in water and soluble in most organic solvents, particularly in dioxane, although of limited solubility in dialkyl ethers and alkyl hydrocarbons.

The pharmacologically active 6-azido-2l-oxygenated-4- pregnene-3,20-diones of this invention, i.e. those 6-azido-4- pregnenes of Formula I wherein Z is hydroxy, acyloxy, or together with Q at C-17 is a 17a,21-alkylidene-dioxy, possess corticoid properties. Of these, the G-aZidO-pregnenes unsubstituted at 0-9 and C-11, i.e. those wherein X and Y are each hydrogen, e.g. 6-azido-16-W-17a-Q-4-pregnene- 2l-ol-3,20-diones of Formula I possess mineralo-corticoid properties and, as such, are useful in the treatment of conditions requiring retention of sodium, e.g. adrenal insufficiency (i.e. Addisons disease) and salt losing syndromes.

Those 6-azido-21-oxygenated-4-pregnene-3,20-diones of the pharmacologically active composition-of-matter aspect of this invention as defined by Formula I which have a halogen or an oxygen function at C-ll possess glucocorticoid activity and are particularly valuable as anti-inflammatory agents. Of these, preferred species are 6-dehydro- 11,17-bis-oxygenated derivatives, particularly 6-azido-4,6- pregnadiene-l7,21-diol-3,20-diones of Formula I wherein Y is (H,fl-OH)- or oxygen analogs thereof, and their ester and 17,2l-alkylidene derivatives, which possess enhanced anti-inflammatory activity.

6 azido-6-dehydrocortisone (i.e. '6-azido-4,6-pregnadiene- 17a,2l-diol-3,11,20-trione, a 6-dehydro compound of Formula I wherein Q and Z are hydroxyl, Y is keto, and W and X are hydrogen) and the 21-acetate; 17- valerate; 17,21-dipropionate, and 17,21-iso-propylidene derivative thereof;

6-azido-'6-dehydrohydrocortisone (i.e. 6-azido-4, 6-pregnadiene-l1,8,17a,21-triol-3,20-dione) and the ZI-acetate; l7-valerate; 17,2l-dipropionate, and the 17,21-isopropylidene-derivative thereof;

6-azido-9a-fiuoro-4,6-pregnadiene-17a,2 l-diol-3,1 1,20-

trione,

6-azido-9a-fluoro-4,6-pregnadiene-l 113,17a,2l-tril-3 ,20

dione,

6-azido-1'6-methylene-4,6-pregnadiene-17a,21-diol-3 ,1 1,20-

trione,

6-azido-16-methylene-4,6-pregnadiene-1 1 3, 17a,2 l-triol- 3,20-dione,

6-azido-9u-fluoro-16methylene-4,6-pregnadiene-1711,21-

diol-3,1 1,20-trione,

6-azido-9a,fluorol6-methylene-4,G-pregnadiene- 1 113,17oz,

21-triol-3,20-dione,

6-azido-l6a-methyl-4,6-pregnadiene-17a,21-diol-3 ,1 1,

20-trione,

6-azido-16,8-methyl4,6-pregnadiene-170:,21-di0l-3, 1 1,20-

trione,

-6-azido-16u-methyl-4,6-pregnadiene-1 113, 17 a,21-triol- 3,20-dione,

6-azido-16p-methy1-4,6-pregnadiene-l 1B,17oc,21-tli01- 3,20-dione,

6-azido-9a-fl'uoro-l6a-methyl-4,6-pregnadiene-17a,21-

diol-3 ,1 1,20-trione,

6-azido-9a-fiuoro-16B-methyl-4,6-pregnadiene-l7a,2l-

diol-3, 1 1,20-trione,

6-azido-9a-fluoro-16B-methyl-4,6-pregnadiene-1 15,17,

21-triol-3,20-dione,

6-azido-16a-hydroxy-4,6-pregnadiene-17a,2l-diol-3, 1 1,20-

trione, the 16,21-diacetate ester thereof, and the 160:, l7a-iso-propylidene derivative thereof,

6-azido-l6a-hydroxy-4,6-pregnadiene -11fi,17a,21 triol- 3,20-dione, the 16,2l-diacetate ester thereof, and the 16a,17a-iso-propylidene derivative thereof,

6-azido-9a-fluoro-1-6a-hydroxy 4,6 pregnadiene 17a, 21-diol-3,1l,20-trione, the 16,21-diacetate ester thereof, and the 16a,l7a-iso-propylidene thereof,

6-azido-9a-fluoro-16/3-methyl-4,S-pregnadiene-l 113, 17a,

21-triol-3,20-dione, the 16,21 diacetate ester thereof, and the 16a,l7a-iso-propy1idene thereof.

The enhanced anti-inflammatory activity of the preferred compounds of this invention, i.e. such as the aforementioned 6-azido-4,6-bis-dehydropregnanes oxygenated at C-ll, C-l7, and C-21, are demonstrated by pharmacological tests in animals. Thus, for example, 6-azido-6- dehydrocortisone 21acetate, when tested for anti-inflamatory activity by the well known systemic pouch test, exhibits anti-inflammatory activity greater than 1.5 times that of prednisolone acetate thus demonstrating 6-azido- 6-dehydrocortisone Zl-acetate about 15 times more active as an anti-inflammatory agent in the systemic pouch test than the corresponding 6-unsubstituted analog, i.e. 6-dehydrocortisone ZI-acetate.

'Ihe 6-azido-9u,l1fi-dihalogeno-4,6 pregnadiene-17,21- bis-oxygenated compounds of the pharma'cologically active composition-of-matter aspect of our invention, i.e. 17a,21-bis-oxygenated compounds of Formula I (especially the -17-monoand 17,21-dilower alkanoate esters thereof) wherein X and Y are halogen, (preferably those wherein the 0-11 halogen (Y) is at least as electronegative as the C-9 halogen (X)), also possess superior anti- 6 inflammatory activity being useful as topical anti-inflammatory agents. Particularly valuable 6-aZidO-9u,11/3-dihalogeno-Z1-oxygenated-4,6-pregnadiene-3,20 diones of our invention include compounds such as:

6-azido-9u,11;8-dichloro-4,6 pregnadiene 1704,21 diol- 3,20-dione, the 21 acetate thereof, the 17-mono-valerate of the l7a,2l-di-propionate thereof, and the 17,2l-isopropylidene derivative thereof,

6-azido-9a,1lB-dichloro-16a-hydroxy 4,6 pregnadiene- 17a,21-diol-3,20-dione, the 16,21-diacetate thereof, and the l6u,l7a-iso-propylidene 2l-acetate thereof,

6-azido-9a,11B-dichloro-16a-methyl 4,6 pregnadiene- 17a,21-diO1-3,20-di0116, the 17-propionate and 17,21-dipropionate esters thereof,

6-azido-9a,11 3-dichloro-l6/8 methyl 4,6 pregnadiene- 17a,2l-diol-3,20-dione, the 17-propionate and 17,21- dipropionate esters thereof, and

6-azido-9a,1lB-dichloro-16-methylene 4,6 pregnadiene- 17a,21-diOl-3,20-di0116.

In addition to the preferred 6-dehydro analogs of the ll-substituted-17,21-oxygenated-4-pregnene-3,20 diones of Formula I listed hereinabo-ve, our invention also includes 6-azido-6,7-dihydro-4-pregnenes, 6-azido-1,4-pregnadienes and 6-azido-1,4,6-pregnatrienes of Formula I having glucocorticoid properties. Typical 6-azido-21- oxygenated-4-pregnene-3,20-diones are compounds such as:

6a-azidocortisone (i.e. 6a-azido-4-pregnene-17a,2l-diol- 3,11,20-trione, a compound of Formula I wherein X and W are hydrogen, Y is oxygen, Q and Z are hydroxy), the 9a-fluoro analog thereof, and their ZI-acetates,

6u-azidohydrocortisone 6a-azido-4-pregnene-1 1,8,17u,21-

triol-3,20,-dione), the 9oc-fll1OI'0 analog thereof, and the Zl-acetates of the foregoing, and

6a azido 90c fluoro 16oz methyl 4 pregnene 11/3, 17u,21-triol-3,20-dione, the 16B-methyl epimer thereof, and the ZI-acetates of the foregoing.

Similarly, typical 6-azido-l,4-pregnadiene-3,ZO-diones of Formula I include compounds such as:

' 6oz azido 1,4 pregnadiene 1712,21 diol 3,11,20-

trione, the 21-acetate and the l7a,21-acetonide thereof, and their 9a-fiuoro derivatives;

60; azido 1,4 pregnadiene llfl,l7a,21 triol 3,20- dione, the 9a-fluoro analog thereof, and their 2l-acetate esters;

6o: azido 16oz methyl 1,4 pregnadiene 170;,21 diol- 3,11,20-trione, the 9a-fluoro analog thereof, and their 21-acetate esters as well as their 17-valerate and 17,21- dipropionate esters;

60c azido 16cc methyl 1,4 pregnadiene 11/3,17u,21-

triol-3,20-dione, the 9oz-fil10l0 derivative thereof, and their 21-acetate esters as Well as their 17-valerate and 17,2l-dipropionate esters;

60a azido 16,9 methyl 1,4 pregnadiene 170:,21 diol- 3,11,20-trione, the 9a-fluoro derivative thereof and their 2l-acetate esters as well as their 17-valerate and 17,21- dipropionate esters;

60c azido 16 8 methyl 1,4 pregnadiene 11/3,17oz,21-

triol-3,20-dione, the 9a-fluoro derivative thereof, and their 21-acetate esters as well as their 17-valerate and 17,2l-dipropionate esters;

60c azido 16 methylene 1,4 pregnadiene 170:,21-

diol-3,11,20-trione, the 9a-fiuoro derivative thereof, and their 21-acetate esters as well as their 17-valerate and 17,21-dipropionate esters;

6m azido l6 methylene 1,4 pregnadiene-l1/3,17a,21-

triol-3,20-dione, the 9oz-fll101'0 derivatives thereof, and

' their 2l-acetate esters and their 17-valerate and 17,21- dipropionate esters, and the 17,2l-acetonide thereof;

60; azido hydroxy 1,4-pregnadiene 17a,21-di01- 3,11,20-trione, the 9a-fluoro derivative thereof, their 16a,2l-diacetate esters, and the l6a,l7a-acetonide derivatives of the foregoing;

6m azido 16oz hydroxy 1,4 pregnadiene 1I}3,l7oz,21-

triol-3,20-dione, the 9a-fiuoro derivatives thereof, their 16a,21-diacetate esters and their l6a,l7a-acetonide derivatives; and

60a azido 941,11}? dichloro 1,4 pregnadiene 1711,21-

diol-3,20-dione, the 17-valerate, the 21-acetate, and the 17,21-dipropionate esters thereof;

60: azido 90;,11/3 dichloro 16oz hydroxy 1,4 pregnadiene-l7a,2l-diol-3,20-dione and the 160:,17oc-3C6- tonides and the l6u,2l-diacetate esters thereof.

Additionally, typical 6-azido-1,4,6-pregnatriene-3,20 diones of Formula I include compounds such as:

6 azido 1,4,6 pregnatriene 170;,21 diol 3,11,20-

trione, the 9a-fill0l0 analog thereof and their 21-acetate esters;

6 azido 1,4,6 pregnatriene 1113,I7oz,21 triol 3,20-

dione, the 9a-fluoro analog thereof, and the 21-acetate esters of the foregoing;

6 azido 16(a or p) methyl 1,4,6 4 pregnatriene-17a, 21-diol-3,ll,20-trione, the 9a-fl11010 analog thereof, and the 21-acetate; 17-valerate; 17,21-dipropionate and 17, 21 -dibutyrate esters thereof;

6-azido-l6(m or ,B)-methyl-1,4,6-pregnatriene-llfl,17 x,2l-

triol-3,20-dione, the 9a-fiu0r0 analog thereof, and the 2l-acetate; 17-valerate; 17,21-dipropionate and 17,21- dibutyrate esters thereof;

6 azido l6-methylene-1,4,6-pregnatriene-l7a,2l-diol-3,

11,20-trione, the 9a-fluoro analog thereof, and the 21- acetate; 17-valerate; 17,21-dipropionate and 17,2l-dibutyrate esters thereof; and

6-azido-16-methylene-1,4,6-pregnatriene-1 lfi,l7a,2l-triol- 3,20-dione, the 9a-fiuoro analog thereof, and the 21- acetate; l7-valerate; 17,21-dipropionate, and 17,21-dibutyrate esters thereof.

In general, the pharmacologically active 6-azido-2loxygenated-4-pregnene-3,20-diones of this invention as de fined by Formula I have an activity similar to that of the corresponding fi-unsubstituted analog and may be administered in similar pharmaceutical forms and for the same indications for which the corresponding 6-unsubstituted- 21 oXygenated-4-pregnene-3,20-diones would be applicable, the total daily dosage depending upon the nature and severity of the inflammation being treated, the age and size of the patient, and the specific activity of the 6-azidocorticoid being administered. When administering preferred compounds of our invention, i.e. 6-azido-6-dehydro-4-pregnenes of Formula I, particularly the ll-oxygenated derivatives thereof, the therapeutic dosages advantageously will generally be lower than those required when administering the corresponding 6-unsubstituted analogs. Thus, for example, 6-azido-4, 6-pregnadiene-17a, 2l-diol-3,11,20-trione, esters, and alkylidenedioxy derivatives thereof, possess anti-inflammatory activity similar to that exhibited by prednisolone and may be administered orally in the form of tablets, capsules, eliXirs, and the like for all inflammatory disorders, particularly arthritis, rheumatism and the like; intravenously in aqueous solution as the 21 hemisuccinate or 21-phosphate ester for the treatment of shock; intramuscularly for long-term systemic activity or intra-articularly for long-term local activity with minimal systemic effects in aqueous suspension as the 17,21-dilower alkanoate esters, e.g. 17,21-dipropionate, and 17,21- di-butyrate; or topically in creams, lotions or ointments as the 17-mono lower alkanoate (e.g. 17-valerate) or as the 17,2l-diesters (e.g. 17,21-di-propionate in the treamtent of contact and allergic dermatitis and psoriasis; or in the form of ophthalmic suspensions or nasal sprays. In each instance, the pharmaceutical dosage forms are prepared according to procedures well known in the art and may contain other active ingredients, e.g. neomycin sulfate in creams for topical use.

CHIC 8 01M wherein M is a hydrocarbon radical having up to seven carbon atoms; and Q, W, X, and Y are as defined in Formula I hereinabove. The 21-hydrocarbonsulfonate ester intermediates of Formula 11 include the ZI-methanesulfonate esters, the 21-ethanesulfonate esters, the 21-benzenesulfonate esters and the 2l-p-toluenesulfonate esters of the 21-hydroxy-6-azido-4,6-pregnadienes defined by Formula I. They are prepared from the corresponding 21- hydroxy precursor utilizing known methods such as that wherein the steroidal 21-alcohol (e.g. 6-azido-6-dehydrocortisone) is treated with a hydrocarbonsulfonyl chloride (e.g. methanesulfonyl chloride) in pyridine at low temperatures whereby is formed the corresponding steroidal 21-hydrocarbonsulfonate (e.g. 6-azido-6-dehydrocortisone 21-methanesulfonate). The hydrocarbonsulfonate esters of Formula II are useful intermediates in the preparation of the 21-phosphate esters of Formula I utilizing procedures analogous to those known in the art. Thus, a 6-azido-4,6-pregnadiene-2l-hydrocarbonsulfonate of Formula II (e.g. 6-azido-6-dehydrocortisone 21-methanesulfonate) upon treatment with sodium iodide in acetone is converted to the corresponding 2l-iodo derivative (e.g. 6-azido-21-iodo 4,6 pregnadiene-.17a-ol-3,l1,20-trione) which upon treatment with phosphoric acid in methanol yields a 21-phosphate ester of Formula II (e.g. 6-azido- 6-dehydrocortisone Ill-phosphate). Because of their solubility characteristics, the 2l-phosphate esters of 6-azidocorticoids of Formula I are particularly valuable for administration via the oral route and the intravenous route as aqueous solutions of their salts.

In addition to the foregoing, the Zl-methanesulfonate esters of Formula II may be used as intermediates in preparing the corresponding 21-unsubstituted steroids since, after conversion thereof of the 2l-iodopregnane as discussed hereinabove, the resulting 6-azido-2l-iodo-4,6- pregnadiene (e.g. 6-azido-2l-iodo-4,6-pregnadiene-l7a-ol- 3,11,20-trione) may be reduced by known methods such as with sodium bisulfite in dioxane to obtain the corresponding 6-azido-progesterone (e.g. 6-azido-4,6-pregnadiene-17u-ol-3,11,20-trione) GENERAL DESCRIPTION OF 6-AZIDO-7-OXYGEN- ATED COMPOSITION-OF-MA'ITER ASPECT OF THE INVENTION The physical embodiments of another composition-ofmatter aspect of this invention include novel 6-azido-7- hydroxypregnanes and 7-esters thereof useful as intermediates in preparing the preferred 6-azido-4,6-pregnadienes of our invention, some of which also have cortical activity. Among the compounds of this invention are members selected from the group consisting of 6fiaZid07a- Q oxygenated-4-pregnene-3,20-diones of following Formula III and the l-dehydro analogs thereof:

wherein V is a member selected from the group consisting of hydrogen and an acyl radical of an acid selected from the group consisting of a hydrocarbon carboxylic acid having up to eight carbon atoms, and a hydrocarbonsulfonic acid having up to 7 carbon atoms;

X is a member selected from the group consisting of hydrogen and a halogen having an atomic weight less than 100;

Y is a member selected from the group consisting of hydrogen, oxygen, (H,flOH), (H43 halogen of atomic weight less than 100) provided X is halogen, (H,aOV') provided X is hydrogen, V being a member selected from the group consisting of hydrogen and an acyl radical of a hydrocarbon sulfonic acid having up to 7 carbon atoms, and Y and X taken together are members selected from the group consisting of a 9(11)-dehydro bond and a 95, lip-epoxy group;

And wherein Q, W, and Z are as defined hereinabove for Formula I.

The acyl radicals contemplated as included within the definition of V in Formula III are those derived from hydrocarbon carboxylic acids having up to 8 carbon atoms including lower alkanoic acids exemplified by formic, acetic, propionic, trimethylacetic, butyric, iso-butyric, tert.-butyric, valeric, iso-valeric, caproic, and caprylic; substituted alkanoic acids such as trifluoroacetic and fi chloropropionic acids, aromatic and substituted aromatic acids such as benzoic, toluic, p-chlorobenzoic, and hydrocarbonsulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

The 1,2-dihydro-compounds of Formula III are useful mainly as intermediates in preparing the preferred 6-azido- 4,6-pregnadienes of our invention via two of the process aspects of our invention. In one, a 6a,7a-oxido-4-pregnene upon treatment with an alkali metal azide is converted to a 6,6-azido-7u-hydroxy-4-pregnene-3,ZO-dione of Formula III which, in turn, is esterified at C-7, and the resulting 6 8-azido 7oz acyloxy-4-pregnene-3,20 dione of Formula III is treated with an alkali metal ammonium fluoride to obtain a pharmacologically active 6-azido-4,6- pregnadiene-3,20-dione of Formula I. In another process, a Gfl-azido-7a-hydroxy-4-pregnene or 6fl-azido-7u-acyloxy- 4-pregnene of Formula III is treated with concentrated hydrochloric acid in acetic acid-dioxane to yield a 6-azido- 4,6-pregnadiene-3,20-dione of our invention.

The physical embodiments of the 6,8-azido-7a-hydroxy 4-pregnene-3,20 dione and 7a-esters thereof of Formula HI, their method of preparation and use as intermediates are described in detail in Examples 1-18, the l-dehydro analogs of Formula HI being prepared in similar manner. The requisite starting 6a,7a-oxido-21-oxygenated-4- pregnene-3,20-diones and l-dehydro analogs are either known compounds or may be prepared via known procedures such as those described in the examples. A convenient method for their preparation comprises treating a 6, 7-unsubstituted-2l-oxygenated 4,6 pregnadiene 3,20- dione or l-dehydro analog thereof with a peracid in a nonreactive organic solvent, e.g. with reagent-solvent combinations such as meta-chloroperbenzoic acid in acetone, meta-chloroperbenzoic acid in methylene chloride/tort.- butanol, or, preferably with mono-perphthalic acid in chloroform.

Typical intermediates of Formula III include compounds such as 6fi-azido-7ot-hydroxy-4-pregnene-17a,21- diol-3,11,20-tri0ne 21-acetate, the 7-acetate ester thereof, the 7-methanesulfonate ester thereof, and the 7-p-toluenesulfonate ester thereof;

6,3-azido-7u-hydroxy-4-pregnene-1 119,170c-l2liO1-3 ,20-dione 21-acetate and the 7-acetate ester thereof;

6/3-azido-7a-acetoxy-9a,1 1fldich1oro-4pregnene-17oz,21-

diol-3,20-dione 21-acetate,

6,8-azido-7a-hydroxy-165-methyl-4-pregnene-17u,21-diol- 3,11,20 trione 21 acetate and the 7-acetate ester thereof;

65-azido-7a-hydroxy-l6-methylene-4-pregnene-170:,21-

diol-3,11,20-trione 2l-acetate and the 7-acetate ester thereof;

6B-azido-7a-hydroxy-4-pregnene-1 1a,17a,21-triol-3,20- dione ll-p-toluenesulfonate 21-acetate and the 7- acetate ester thereof;

6fl-azido-7a-acetoxy-9BJ 1 fl-oxido-4-pregnene- :,21-

diol-3,20-dione 21-acetate;

6fl-azido- 7u-acetoxy-4,9 1 1 -pregnadiene- 170:,21-

diol-3,20-dione 21-acetate.

In addition to the foregoing, the 4-dehydroand 1,4- bis-dehydro-steroids of Formula HI possess corticoid activity except those wherein Y is (H,aOV') or wherein X and Y together comprise a double bond or a 95,11,8- epoxy group, all of which are useful mainly as intermediates. The compounds of Formula III are therefore useful for the treatment of conditions requiring corticoid therapy in a manner similar to that described hereinabove for the corresponding 6-azido-21-oxygenated-4,6-pregnadiene-3,20-diones of Formula I. Of the 6/3-azido-7a-hydroxy-4-pregnenes and 1,4-pregnadienes of Formula III, those preferred as corticoid therapeutic agents are those substituted at C-11 by a halogen, oxygen, or beta-hydroxyl which possess anti-inflammatory activity as demonstrated by tests in animals. Thus, when evaluated by the known systemic rat pouch test, 6B-azido7a-hydr0Xyc0rtisone 21- acetate (compound of Formula III wherein X, V and W are hydrogen, Y is oxygen, Q is hydroxyl and Z is acetoxy) demonstrates an anti-inflammatory activity about 2.5 times greater than that of cortisone; similarly, 6B- azido-7a-hydroxy-prednisone 21-acetate (a l-dehydro analog of Formula III wherein V, X and W are hydrogen, Y is oxygen, and Z is acetoxy) demonstrates over about 5 times the anti-inflammatory activity of cortisone.

GENERAL DESCRIPTION OF ONE PROCESS AS- PECT OF PREPARATION OF 6-AZIDO-4,6-PREG- NADIENES The preferred 6-azido-4,6-pregnadiene-3,20-diones of our invention, i.e. the 6-dehydro analogs of Formula I, are conveniently prepared from the corresponding 606,70:- epoxy-4-pre'gnene derivatives wherein the 21 hydroxy group is preferably protected by an ester group or by formation of a l7oc,2l-alkylidenedioxy derivative (e.g. 6oc,7aoxidocortisone 21-acetate and 6a,7a-oxido-17a,2l-iso-propylidenedioxy-4-pregnene 3,20 dione, respectively) via the process aspect of our invention shown diagrammatically below in Chart A wherein substi-tuents Q, W, X, Y, and Z in structural Formulae A, B, and C are as defined hereinabove for Formula I and wherein I is a G-dehydro analog of Formula I:

Acylating medium --O acyl Chart A According to our process, as shown diagrammatically hereinabove, a ,7oc-OXidO-90c-X-1lB-Y-16-W-17a-Q-2l- Z-4-pregnene-3,20-dione (Formula A) (e.g. 6a,7a-oxido- 4-pregnene-17m,21-diol 3,11,20 trione ZI-acetate) is treated with an alkali metal azide (e.g. sodium azide) in a non-reactive, organic solvent, preferably a solvent mixture in which water is present (e.g. aqueous methanol, aqueous methanol/dioxane, aqueous dioxane, aqueous tetrahydrofuran, and the like) under mild conditions in neutral, or slightly basic or slightly acidic media whereby the epoxy function is split and there is introduced into the molecule a 6B-azido-7a-hydroxy system to form a novel intermediate of our invention, i.e. a 6,8-azido-7a-hydroxy-4-pregnene of Formula B (e.g. 6/3-azido-7a-hydroxy-4-pregnene-17a,21-diol-3,1 1,20-trione 21-acetate.

The 7a-hydroxy function in the thereby formed 6,8- azido-7u-hydroxy-9a-X-llfi-Y-l6-W-17a-Q-21-Z-4 pregnene-3,20-dione (Formula B) (e.g. 6p-azido-7u-hydroxy- 4-pregnene-17a,21-diol-3,11,20-trione 2l-acetate) is then esterified utilizing known esterification procedures (e.g. that utilizing acetic anhydride in pyridine). Treatment of the resulting 6fl-azido-7 x-acyloxy-9a-X-11fi-Y-16-W-17a- Q-21-Z-4-pregnene-3,ZO-dione (Formula C), a novel intermediate of our invention (e.g. 6p-azido-7u-acetoxy-4-pregnene-17a,21-diol-3,20-dione Zl-acetate) with a tetraalkylammonium halide (e.g. tetramethylammonium fluoride) in an aprotic solvent, preferably acetonitrile or dimethylformamide, yields a pharmacologically active 6-azido-9u- X-l Iii-Y-l6-W-17a-Q-21-Z-4,6-pregnadiene 3,20 dione of our invention (Compound I), e.g. 6-azido-4,'6-pregnadiene-17a,21-diol-3,11,20-trione 21-acetate.

Our process provides a convenient, novel method of converting, in good yields, a 6a,7a-epoxy-4-pregnene to the novel, pharmacologically active 6-azido-4,6-pregnadienes of our invention. Heretofore, it has been unknown to deacetoxylate a 6-substituted-7a-acyloxy-4-pregnene with a tetraalkylarnmonium halide to obtain a 6-substituted-4,6-pregnadiene. We have found, however, that when a 6,8-azido-7a-acyloxy-4-pregnene-3,20-dione of Formula III (or Formula C hereinabove) is treated with a tetraalkylammonium halide (e.g. tetramethylammonium fluoride) in an aprotic solvent according to a process aspect of our invention, there is formed, in good yield, a 6-azido-4,6-pregnadiene of Formula I.

In carrying out the first step of the aforedescribed process whereby a 6a,7u-oxido-21-oxygenated-4-pregnene- 3,20-dione of Formula A is converted to a 6,8-azido-7uhydroxy-Zl-oXygenated-4-pregnene-3,20-dione of Formula B, the alkali metal azide reagent of choice is sodium azide, although there maybe used other alkali metal azides such as potassium azide, lithium azide; alternatively, there may also be used quaternary ammonium azides such as tetrabutylammonium azide.

The solvents used in the epoxide splitting step may be any non-reactive, organic solvent in which the steroidal starting compound and the azide reagent are soluble. By non-reactive, organic solvent is meant an organic solvent which will not react with an alkali metal azide or the steroid substrate under the conditions of the reaction so as to cause transformations which will result in the occurrence of competing side reactions. Included among the non-reactive organic solvent contemplated for the epoxide opening are hydroxylated hydrocarbons (e.g. methanol and tertiary butanol), cyclic ethers (e.g. dioxane) and N,N-dialkyl amides (e.g. dimethylformamide).

The epoxide-splitting step is carried out under mild conditions, usually at temperatures ranging from about 0 C. to about 55 C. and preferably at room temperature, with the reaction media usually being maintained at about neutrality (e.g. utilizing dimethylformamide and sodium azide) or slightly basic (e.g. utilizing methanol with sodium azide) or slightly acidic (e.g. utilizing dioxane and methanol as solvent together with a small quantity of aqueous lower alkanoic acid or, alternatively of aqueous boric acid). When carrying out this step on a compound of Formula A having primary or secondary ester groups, e.g. compounds wherein Z is acyloxy and/or W is ('H,rx-acyloxy), in order to minimize hydrolysis of the ester function, the epoxide opening step is advantageously carried out in the presence of acid, preferably an acid having the same acyl function as that in the ester groups in the starting steroid A. Thus, 60:,7rx-OXidOCOItisone Zl-acetate upon treatment with sodium azide in aqueous methanol/dioxane to which a few milliliters of acetic acid are added yields a ZI-acetate of Formula B, e.g. 6p-azido-7a-hydroxycortisone 2l-acetate. Alternatively, when carrying out this step on a compound of Formula A having an alkylidenedioxy function (i.e. 17,21- alkylidene derivatives of compounds wherein Q and E are hydroxy and 16,2l-alkylidene derivatives of compounds wherein Q and W are hydroxy) in order to minimize hydrolysis of the alkylidenedioxy function, the epoxide opening step is advantageously carried out under essentially neutral or slightly basic conditions. Thus, 60:, 7a oxido-l701,2l-isopropylidenedioxy-4-pregnene-3,1 1,20- trione (compound of Formula A) upon treatment with sodium azide in aqueous methanol/dioxane yields a 17cc,

21-alkylidenedioxy derivative of Formula B, 6fi-azido-7ahydroxy-l7,2l-isopropylidenedioxy-4-pregnene 3,11,20 trione.

In a preferred procedure of carrying out the epoxide opening step of our processes for preparing 6-azido-4,6- pregnadienes there is usually added to a solution of the 6a,7a-oxido-2l-0xygenated-4-pregnene-3,ZO-dione (A) in a non-reactive solvent or solvent mixture (e.g. methanoldioxane mixture) at least one mole of alkali metal azide per mole of steroid (preferably 10 to 12 moles of azide per mole of steroid) in a minimum of aqueous lower alkanoic acid, e.g. acetic acid (usually about 100 ml. water and about 1 ml. acetic acid per mole alkali metal azide) and the reaction mixture is allowed to stand at room temperature until all the starting material is transferred as determined by thin layer chromatography (usually about 17 hours). The desired 6/3-azido-7whydroxy thereby formed (B) is then conveniently isolated by pouring the reaction mixture into water, extracting the aqueous mixture with an organic solvent, evaporating the combined organic extracts to a residue comprising a 6,8-azido 7m hydroxy-Z1-oxygenated-4-pregnene-3,20- dione of Formula B (also a compound of Formula III). Purification is effected utilizing known techniques including crystallization and thick layer chromatography.

The esterification step of our process (i.e. B- C) is usually carried out in basic media, under relatively mild conditions known to esterify secondary hydroxyl groups. Preferably, the esterificafion is carried out at room temperature in pyridine utilizing large molar excesses of acylating agents which may be an acid halide of an aryl carboxylic acid (e.g. benzoyl chloride) or of a hydrocarbonsulfonic acid (e.g. p-toluenesulfonyl chloride or methanesulfonyl chloride) or an acid anhydride of a lower alkanoic acid having up to eight carbon atoms. In a preferred procedure for carrying out this step whereby the 7u-hydroxy function is esterified, Whenever starting steroid (B), already possesses an ester function, the acylating agent used is preferably one having the same acyl radical as that in the starting steroid (B) (e.g. acetic anhydride when the starting steroid (B) is 6p-azido-7u-hydroxy-4-pregnene-17 uc,21-diU1-3,1 1-20-triene 21-acetate) The last step of our process whereby a 6fl-azido-7uacyloxy-21-oxygenated-4-pregnene-3,20-dione (C) upon treatment with a tetraalkylammonium halide is converted to a 6 8azido- 21-oxygenated-4,6-pregnadiene-3,20-dione (I), is usually carried out in an aprotic solvent at temperatures in the range of from about 0 C. to about 80 C preferably between 20 C. to about 60 C.

Although anhydrous conditions are usually employed for this last deacylating step of our process, water may be present in small amounts, and there will be formed the desired 6-azido-4,6-pregnadiene.

Thus, treatment of 6p-azido-7a-acetoxy-4-pregnene 17,2l-diol-3,11,20-trione 21-acetate in acetonitrile with tetramethylammonium fluoride pentahydrate yields 6- azido-4,6-pregnadiene l7a,21-diol-3,l1,20-trione 21-acetate in good yield.

Aprotic solvents suitable for use in our process include dimethylsulfoxide, dimethylacetamide, dioxane, tetrahydrofuran, and preferably acetonitrile or dimethylformamide.

Tetraalkylammonium halides are known in the art. In our process, we have found it most convenient to use tetramethylammonium chloride or, preferably, tetramethylammonium fluoride, since they are commercially available and excellent product yields are obtained thereby. When utilizing the commercially available tetramethylammonium fluoride pentahydrate as reagent, usually the water of hydration is removed therefrom by azeotropic distillation with acetonitrile although the reaction will proceed when the pentahydrate is used as reagent. When preparing the anhydrous form of the tetramethylammonium fluoride reagent, the azeotropic distillation is continued until the reagent is a solid at 50 C., at which point it is most suitable for use as a deacyloxylating reagent to convert a 6fi-azido-7a-acyloxy-2l-oxygenated-4-pregnene- 3,20-dione to a 6-azido-6,7-unsubstituted-2l-oxygenated- 4,6-pregnadiene-3,20-dione (I) of our invention.

The tetraalkylammonium halide reagents have limited solubility in the aprotic solvents utilized in this process; therefore, it is preferable to stir the reaction mixture when deacyloxylating at C-7 (6). The reaction will proceed without stirring, however, with the tetraalkylammonium halide dissolving as the reaction proceeds.

Generally when deacyloxylating a 6fi-azido-7u-acyloxy- 21-oxygenated-4-pregnene-3,20 dione of Formula C, the 6/3-azido-7a-acyloxy intermediate (C) is added (either in the solid state or in solution) to a solution or suspension of tetraalkylammonium halide (present in quantities ranging from 1.5 moles to 5 moles per mole of steroid) in an aprotic solvent (of which 1 ml. per 10 mgm. of reagent is generally used). The reaction is stirred or left standing in temperatures ranging between 0 C. to C. until the deacyloxylation at C-6 (7) is completed as evidenced by thin layer chromatography or by spectroscopic evaluation. (Reaction times usually range from 10 minutes to 48 hours.) The resulting 6-azido-2l-oxygenated-4,6-pregnadiene-3,20-dione of Formula I is isolated utilizing known techniques. Usually, the solvent is partially or totally removed in vacuo, then an organic solvent (e.g. methylene chloride, chloroform, ethyl acetate, and the like) is added, the solution poured into water, the layers separated, the organic layer washed with dilute aqueous base (e.g. sodium bicarbonate), dried and evaporated to a residue comprising the desired 6-aZidO-9u-X-11-Y-16-W-17a-Q-21- oxygenated-4,6-pregnadiene-3,20-dione of Formula I. Purification of this product is effected by known techniques including chromatography and recrystallization methods.

In our process whereby a 6a,7a-oxido-21-oxygenated-4- pregnene-3,20-dione is converted via three steps to a 6- azido-21-oxygenated-4,6-pregnadiene-3,20-dione, the necessary 6a,7a oxide-21-oxygenated-4-pregnene-3,20-dione starting compounds (A) are conveniently prepared according to known procedures from the corresponding 6,7- unsubstituted-2l-oxygenated-4,6-pregnadiene 3,20-di0ne such as by reaction with a peracid in a non-reactive organic solvent, e.g. with reagent-solvent combinations such as meta-chloroperbenzoic acid in acetone, meta-chloroperbenzoic acid in methylene chloride/tert.-butanol, or with mono-perphtha1ic acid in chloroform.

The 6,7-unsubstituted-2l-oxygenated 4,6-pregnadiene- 3,2-O-dione precursors of the starting 60:,7ot-OXidO intermediates (A) are a known class of compounds conveniently derived from the corresponding 6,7-dihydro analogs by procedures known to efiect dehydrogenation between 0-6 and C-7, such as those utilizing chloranil or 2,3-dichloro-S,6-dicyanobenzoquinone (DDQ). When the starting steroid has a 16-alkyl substituent, e.g. l 6/3-methyl-4- pregnene-l7a,2l-diol-3,11,20-trione 21-acetate, in order to minimize the possibility of rearrangement reactions, introduction of the 6-dehydro bond is preferentially effected by the use of 2,3-dichloro-5,G-dicyanobenzoquinone in the presence of acid (e.g. DDQ in ethyl acetate and acetic acid).

When preparing the preferred 6-azido-2l-oxygenated- 4,6-bis-dehydropregnanes of our invention (i.e. the 6-dehydro analogs of Formula I) by the above described process, it is usually preferable to have present in the starting 611,71 epoxypregnane (A) all the substituents desired in the final 6-azido-4, G-pregnadiene product, I.

Alternatively, substituents such as those at (3-9 and C-ll may be introduced into the molecule during the process, preferably after the formation of the GB-azido- 7ot-acyloxypregnane intermediate (C). Thus, to prepare a 6-azido-9a,1l{3-dihalogeno-4,-6-pregnadiene of Formula I, e. g. 6-azido-9a,1lp-dichloro-4,6-pregnadiene-170,2l-di0l- 3,20-dione 2l-acetate, one may utilize as starting compound the known 6a,7u-oxido-llot-tosyloxy-4-pregnene- 17a,2l-diol-3,20-dione 2l-acetate which may be converted via the above process to the corresponding 6,8- azido-7u-hydroxy-4-pregnene and thence esterified at C-7 to form 6B-azido-7a-acetoXy-l1a-tosyloxy-4-pregnene-17a, 21-diol-3,20-dione. Desulfonyloxylation at C-ll according to known procedures such as that utilizing sodium acetate in acetic acid yields the corresponding 9(ll)-dehydropregnane, i.e. 6fi-azido-7a-acetoxy-4,9( l l )-pregnadiene-17ot,21-diol-3,20-dione 2l-acetate, a compound useful as an intermediate in preparing 9a-halogeno-11fl-hydroxy derivatives as well as 9a,l1[3-dihalogeno compounds of Formula I.

When the lla-tosylate precursor is not readily available, the 9( 11)-bond may be introduced into the molecule, utilizing known procedures preferably before formation of the 6-azido-6-dehydro-system and after the epoxidation at C-6 and 7, usually after preparation of the 6fi-flZldO-70cacetoxypregnane intermediate. Thus, an ll-hydroxyl group is introduced microbiologically with the aid of microorganisms such as Curvularia lunata (N.R.R.L. 2380) or Rhizopus nigricans (A.T.C.C. 6227b). When Curvularia lunata is employed, the llfi-hydroxy steroid produced is dehydrated by a reagent such as methanesulfonyl chloride in the presence of pyridine or phosphorous oxychloride in pyridine or N-bromoacetamide and sulfur dioxide in pyridine to give the 9(ll)-dehydro intermediates. Alternatively, the action of Rhizopus nigricans on a corticoid such as l6a-mcthyl-4-pregnene- 17oz,21di01-3,20-di0[18 21-acetate yields the Ila-hydroxy derivative, 16a methyl-4-pregnene-lla,l7ot,21-triol-3,20- dione. After reacetylation at C-2l, subsequent treatment with a sulfonyl chloride such as methanesulfonyl chloride yields the corresponding lla-sulfonate, i.e. Ila-methanesulfonyloxy 16oz methyl 4 pregnene 17a,21-di0l- 3,20-dione ZI-acetate. To minimize the possibility of competing side reactions, the first two steps in our process for introduction of the 6-azido-6-dehydro-system are carried out with the 1la-sulfonyloxy-derivative. Thus, treatment of 11a methanesulfonyloxy 16a methyl-4- pregnene 17a,21 diol 3,20 dione 2l-acetate with chloranil followed by epoxidation of the 6-dehydro analog thereby formed, i.e. lla-methanesulfonyloxy-l6a-methyl- 4,6 pregnadiene 17a,2l diol 3,20 dione 21-acetate, with mono-perphthalic acid, for example, yields 6a,7aoxido 11a methanesulfonyloxy 16cc methyl 4- pregnene l7a,21 diol-3,20-dione 21-acetate which, upon treatment with sodium azide yields 6B-azido-7a-hydroxyllamethanesulfonyloxy 16a methyl 4 pregnene- 17ot,21-diol-3,20-dione 21-acetate. Esterification at -7 utilizing acetic anhydride in pyridine yields 6fi-azido-7aacetoxy lla methanesulfonyloxy 16a methyl-4- pregnene 17cc,21 diol-3,20-dione 21-acetate. Introduction of the 9(ll)-bond is conveniently carried out in the foregoing lla-methanesulfonate by treatment with sodium acetate in acetic acid to yield 6/3-azido-7a-acetoxy- 16a methyl-4,9(l1)-pregnadiene-17a,2l-diol-3,20-dione 2l-acetate.

After formation of the 9(ll)-dehydro intermediate, halogen groups may then be introduced at C9 and C-11 of the 6,8 azido 7a acetoXy-4,9(ll)-pregnadiene-l7a, 21-diol-3,20-dione 21-acetate, e.g. to form a 9a,1l 8-dichloro derivative employing procedures Well known in the art. For example, treatment of the aforenamed 9(ll)- dehydropregnanes with chlorine in halogenated solvents such as methylene chloride will yield the 9a,11,8-dichloro intermediates, 6n azido 7a-acetoxy-9a,11fl-dichloro-4- pregnene 17ot,21-di01-3,20-di0l16 Zl-acetate, and the 16tx-methyl homolog thereof which upon treatment with tetramethylammonium fluoride as described in Example 6B herein, will yield 6-azido-9a,l1B-dichloro-4,6-pregnadiene 17a,2l diol 3,20 dione 2l-acetate, a -dehydro compound of Formula I. If a 9m-bromo-11B-fluoroor a 90: chloro 115 fluoro-derivative is desired, the 6B- azido 70c acyloxy 9(ll) dehydro precursor is treated with N-bromo-succinimide and hydrogen fluoride or N-chlorosuccinimide and hydrogen fluoride, respectively, to obtain the corresponding 9u,1l}3-dihalogeno derivative, i.e. 65 azido 7a-acetoxy-9a-bromo-l1 8-fluoro-4- pregnene 170;,21 diol 3,20 dione 2l-acetate and 6,3 azido 7a acetoxy 9o: chloro-11,6-fluoro-4- pregnene 170;,21 diol 3,20 dione 21-acetate, respectively, and the methyl homologs. Treatment of each of the foregoing 65 azido 7a-acetoxy intermediates with tetramethylammonium fluoride according to the above described process yields 6-azido-6-dehydro-9a,l113- dihalogeno derivatives of Formula I, e.g. 6-azido-9abromo 11p fluoro 4,6-pregnadiene 17a,21-diO1-3,20- dione 21 acetate and 6 azido 9oz chloro-llfl-fluoro- 4,6 pregnadiene :,21 diol 3,20 dione 2l-acetate, respectively, and their 16a-methyl homologs.

The 6/3 azido 7oz acetoxy-9(ll)-dehydropregnanes are also useful in the preparation of the 9a-halogeno-11B- hydroxy derivatives of our invention. Thus, a 6p-azido- 7a acetoxypregnane (e.g. 613 azido 7a acetoxy-4, 9(11)-pregnadiene-17a,21-diol-3,20-dione 21-acetate) and the 16a-methyl homolog thereof upon treatment with N- bromoacetamide in aqueous dioxane in the presence of perchloric acid according to known procedures yields the corresponding 9a-bromo-115-hydroxy derivative (e.g. 6B- azido 7a acetoxy 9a bromo-1lfi-hydroxy-4-pregnene- 1704,21 diol 3,20 dione 21-acetate and the 16a-methyl homolog thereof).

Other 9a halogeno 11B hydroxy 6 3-azido-7aacetoxy 21 oxygenated-pregnane intermediates, i.e. the Qa-ChiOIO- and 9a-fltl0IO-, are obtained from the corresponding 9/8,1l,B-0Xido derivatives, e.g. 6,6-azido-7uacetoxy 9 8,11p-oxido-4-pregnene-17a,2l-diol-3,20-dione 21-acetate which, in turn, are derived from the aforedescribed 90c bromo 11,8 hydroxy intermediates, e.g. 6B azido 70c acetoxy 90c bromo llfi-hydroxy-4- pregnene 1711,21 diol 3,20 dione 21-acetate, by treatment with potassium acetate in ethanol or acetone. Addition of hydrogen chloride in chloroform, or of hydrogen fluoride in chloroform-tetrahydrofuran, to a 9B, llp-oxido pregnane intermediate, e.g. 65 azido 7aacetoxy 96,1lp-oxido-4-pregnene-17u,21-diol-3,20-dione 2l-acetate, will yield the corresponding 9a-chloro-l1fi-hydroxyor 9a-fiuoro-llfi-hydroxy-pregnane intermediates, respectively, e.g. 6B azido 7a-acetoxy-9u-chloro-4- pregnene 11p,17a,2l-triol-3,20-dione ZI-acetate, and 618- azido 7a acetoxy 9a fluoro-4-pregnene-115,17a, 2ltriol-3,20-dione 2l-acetate.

By utilizing the above procedures it is obvious that one need but choose the appropriate 6p-azido-7a-acetoxy-9- (1l)-dehydro-intermediate to obtain other 9a-hal0genol1fi-hydroxy-6/3-azido-7a-acetoxy-pregnane intermediates of our invention. The 6fl-azido-7u-acyloiry-9 llfl-dihalogeno-pregnanes and the 6p-azido-7ot-acyloXy-9ot-halogenollfl-hydroxy-pregnane intermediates prepared from the corresponding 6,B-azido-7a-acyloxy-9(11) dehydropregnanes as described hereinabove are then converted to the corresponding 6-azido-4,6-pregnadienes of our invention by treatment with a tetraalkylammonium halide in acetonitrile. Thus, each of the 6l3-azido-7a-acetoxy-9a-bromo- 4-pregnene-11B,l7a,2l-triol-3,20-dione 2l-acetate, 6fi-azido-7a-acetoxy-9a-chloro-4-pregnene 11B,17oz,21 triol- 3,20-dione ZI-acetate and 6B-azido-7a-acetoxy-9a-fluoro- 4,6-pregnadiene-11B,17 x,21-triol 3,20 dione 21-acetate and the 16 (a and fi)-methyl homologs thereof upon treatment with tetramethylammonium fluoride in acetonitrile yields the corresponding 6-azido-9a-halogeno-l1/3- hydroxy-4,6-pregnadieneof our invention, e.g. 6-azido- 9a-bromo-4,6-pregnadiene 11B,17a,21 tri01-3,20-dione 2l-acetate, 6-azido-9a-chloro-4,6-pregnadiene-1 1fl,17u,21- triol-3,20-dione 2l-acetate, and 6-azido-9a-fluoro-4,6-pregnadiene-l1 8,17a,21-triol-3,20-di0ne 21-acetate, respectively, and the 16(a and SD-methyl homologs thereof.

When the starting 6p-azido-7u-acetoxy-4-pregnane has a 9oc-bromo-11B-hydroxy group, treatment with tetramethylammonium halide according to our process will cause the formation of a mixture of products including some 9;9,11fl-oxido-4,6-pregnadiene. Separation of the product mixture may be effected via chromatographic procedures. Thus, treatment of 6B-azido-7a-acetoxy-9u-bromo-1lfi-hydroxy-4-pregnene-l7a,21-diol 3,20 dione 21-aoetate with tetramethylammonium fluoride in acetonitrile yields a mix: ture of 6-azido-9a-bromo-11fl-hydroxy-4,6-pregnadiene. 17a,21-diol-3,20-dione 21-acetate together with some 6- azido-9/3,11fl-oxido 4,6 pregnadiene-17a,21-diol-3,20- dione ZI-acetate which, when separated on a thick layer preparative plate with silica gel yields mainly 6-azido9abromo-llB-hydroxy 4,6 pregnadiene-17a,21-diol-3,20 dione 21-acetate.

The 9a-halogeno-1l-keto-pregnanes of Formula I may be obtained from the 9a-halogeno-1lp-hydroxypregnanes by oxidation of the ll-hydroxy function such as with chromic acid. Alternatively, the 6-azido-9u-halogeno-11- keto-4,6-pregnadienes may be obtained from the 6a,7aoxido-4-pregnene-precursor according to the process described hereinabove. Thus, 6-azido-9a-fluoro-4,6-pregnadiene-17u,21-diol-3,11,20-trione 21-acetate is formed upon oxidation of 6-azido-9u-fluoro-4, 6-pregnadiene-1 1 13, 17 a,21- triol-3,20-dione 21-acetate with chromic acid. Alternatively, this 9oz-fluoro-1l-ketopregnane is derived from 6a,7uoxido-9a fluoro-4-pregnene17a,21-diol-3,l1,20 trione 21- acetate which upon treatment with sodium azide in dilute acetic acid is converted to the corresponding 6fi-azido-7uhydroxy intermediate, i.e. 6ft-azido-7u-hydroxy-9a-fiuoro- 4-pregnene-17u,21-diol 3,11,20 trione 21-acetate, which after esterification at C-7, such as with acetic anhydride in pyridine, followed by treatment of the thereby formed 7u-acetate ester with tetramethylammonium fluoride yields the 6-3ZiClO-9u-flll0l'O-l1-k6t0 4,6 pregnadiene of Formula I, i.e. 6-azido-9a-fluoro-4,6-pregnadiene-170;,2l-diol- 3,1 1,20-trione 21-acetate.

GENERAL DESCRIPTION ANOTHER PROCESS ASPECT FOR PREPARATION OF 6-AZIDO-4,6- PREGNADIENES.

The preferred compounds of this invention, i.e. the 6- azido-Zl-oxygenated-4,6-pregnadiene 3,20 diones of Formula I are also prepared from the 6B-azido-7a-hydroxy-4-pregnene or the Gil-azido-7a-acyloxy-4-pregnene intermediate of the first process aspect (Formulae B and C, Chart A hereinabove) (of which the 21-hydroxy group is preferably protected by an ester group or by formation of a 17a,21-alkylidenedioxy derivative) by reaction of said 6/3-azido-7u-hydroxy-4-pregnene of Formula B or the 7mester thereof with concentrated hydrochloric acid in acetone or preferably, in a solvent mixture comprising a lower alkanoic acid (e.g. acetic acid) and dioxane.

In carrying out the physical embodiment of this process aspect, we have found that concentrated hydrochloric acid is necessary in order to dehydrate at C-6 and C-7, i.e. to convert the 613-azido-7a-hydroxy pregnane or 6p-azido-7aacyloxy pregnane to a 6-azido-6-dehydro pregnane. When other acids are employed such as p-toluenesulfonic acid or sulfuric acid, dehydration doesnot occur and the 6fl-azido- 7 a-hydroxy or 6 3 -azido-7oc-acyloxy starting compound (B) is recovered even after several days reaction time.

. According to our process, a 6/3-azido-7a-hydroxy-9u- X-l1/3-Y-1'6-W-17a-Q-21-Z-4-pregnene 3,20 dione (Formula B, Chart A) or a 7a-acyloxy thereof (Formula C, Chart A) is dissolved in either acetone or preferably a solvent mixture comprising a lower alkanoic acid (usually acetic acid) and dioxane to which concentrated hydrochloric acid is added. The reaction mixture is allowed to remain at room temperature until a thin layer chromatographic analysis of an aliquot of the reaction mixture indicates the absence of a fifl-azido-h-hydroxy or a 6p-azido- 7 a-acyloxy intermediate. The reaction time is usually from ing the residue via chromatographic techniques.

The 6fl-azido 7a hydroxy-4-pregnene-3,20-diones of Formula B, and the 6B-azido7uacyloxy-4-pregnene-3,20- diones of Formula C (or III shown hereinabove), necessary intermediates in this process aspect, are prepared in the same manner as described hereinabove in the section relating to the first process aspect.

In carrying out the physical embodiment of this process aspect whereby a 6a,7a-oxido-4-pregnene-3,20-dione of Formula A is treated with an alkali metal azide in a nonreactive organic solvent and the thereby formed Gil-azido- 7u-hydroxy-4-pregnene precursor (Formula A) desirably ought possess the substituents, (such as at 0-9, 11, 16 and 17) which are desired in the 6-azido-4,6-pregnadiene product of Formula I produced thereby. When structural modifications of the pregnane molecule (such as at 0-9 or 11) are contemplated, it is usually preferable to utilize as starting compound a 6fl-azido-7m-acryloxy-4-pregnene of Formula III (or Formula C) hereinabove and, after carrying out any desired structural modifications on the 7m-acyloxy intermediate, converting the thereby modified steroid (e.g. a 6,3-azido-7a-acyloxy-9u-X-l1-Y-16-W-17a- Q-21-Z-4-pregnene-3,ZO-dione of Formula III) to the therapeutically active 6-azido-4,6-pregnadiene of Formula I by treatment thereof with concentrated hydrochloric acid or, preferably, with a tetraalkyl ammonium halide according to the first process aspect of four invention.

GENERAL DESCRIPTION OF THE PROCESS FOR PREPARING 6oz AZIDO 21 OXYGENATED 4- PREGNENE-3,20-DIONES AND THE l-DEHY- 'DRO ANALOGS THEREOF The 6,7-dihydro-6a-azido-2l-oxygenated-4-pregnenes of Formula I and the l-dehydro analogs thereof are prepared from a corresponding 6-substituted derivative, preferably a 6fl-bromo-, a 6i3-chloro-, or a 6B-hydrocarbonsulfonyloxy-21-oxygenated-4-pregnene having up to seven carbon atoms, according to yet another process aspect of our invention whereby a 6B-halogenoor a 6 3-hydrocarbonsulfonyloxy- 21 oxygenated-4-pregnene-3,20-dione or a l-dehydro analog thereof is treated with an alkali metal azide (preferably sodium azide) in a non-reactive solvent whereby there occurs replacement with inversion of the halogen or hydrocarbonsulfonyloxy at 0-6 by azido and there is formed the corresponding 6u-azido-21-oxygenated- 4-pregnene-3,20-dione.

In this process aspect of our invention, as in the first process aspect, the alkali metal reagent of choice is sodium azide, although there may be used other alkali metal azides such as potassium azide, lithium azide, or quaternary ammonium azides such as tetrabutylammonium azides.

Solvents suitable for use in this process are any nonreactive, organic solvent in which the starting 6-substituted-2l-oxygenated-4-pregnene and the alkali metal azide reagent are soluble. The term non-reactive means any organic solvent which will not react with the steroid substrate or the azide reagent so as to cause transformations which will result in competing side reactions. Included among non-reactive solvents contemplated for this process aspect of our invention are hydroxylated hydrocarbons (e.g. methanol, ethanol, etc.) including glycols such as ethyleneglycol-monomethyl ether, cyclic ethers (e.g. dioxane), dialkyl amides (e.g. dimethylformamide, diethylformamide, etc.), dialkylsulfoxides (e.g. dimethylsulfoxide), and solvent mixtures such as dioxane-water, and dioxane-water-ethanol.

The replacement process whereby a 618-chloro-, 6pbromo-, or 6,8-hydrocarbonsulfonyloxy-4-pregnene is replaced by a Got-azido group is usually carried out under mild conditions, usually in temperatures ranging from about 20 C. to about 80 C. with the reaction mixture being stirred for from about 15 minutes to about 2.5 hours, or until the reaction is complete as evidenced by thin layer chromatographic techniques.

Our process is preferably (although not necessarily) carried out under an atmosphere of an inert gas such as argon, krypton, or nitrogen.

Generally, when preparing a 6a-azido-21-oxygenated-4- pregnene-3,20-dione of Formula I (e.g. ou-azidoprednisone 21-acetate, i.e. a-azido-lA-pregnadiene-1701,21- diol-3,11,20-trione 21-acetate) by our process, the alkali metal azide reagent (e.g. sodium azide) is added to a solution or suspension of a corresponding 6,B-halogeno derivative (e.g. 6,8-bromo 1,4 pregnadiene-17a,2l-diol-3,20- dione 21-acetate or the corresponding 6 3-chloro derivative), or 6/8-hydrocarbonsulfonyloxy (e.g. methanesulfonyloxyor p-toluenesulfonyloxy-), the quantities of re-, agent ranging from 1 to 20 moles of alkali metal azide per mole of steroid, and preferably 1 to 3 moles of alkali metal azide per mole steroid when the starting steroid is substituted at -9 by bromine or chlorine and at C-ll by hydroxyl, chlorine or bromine when a halogen is present at C-ll, equimolar quantities of alkali metal halide and 6p?- halogeno-4-pregnene intermediate are advantageously employed to avoid side products caused by replacement of the llfi-halogeno by azido. The reaction is preferably carried out under an inert atmosphere (e.g. under nitrogen) at temperatures in the range of from about 20 C. to about 80 C. and usually at about room temperature until the replacement of 6 8-halogeno or 6fi-hydrocarbonsulfonyloxy by Got-azido is complete as evidenced by thin layer chromatographic analysis. (Reaction time usually takes from 45 minutes to about 2 hours. The resulting 6u-azido-21-oxygenated-4-pregnene-3,20-dione of Formula I (e.g. 6a-azido-1,4-pregnadiene-17a,21-diol-3,20- dione 21-acetate) is isolated utilizing known techniques. Usually, the reaction mixture is poured into a large volume of water and the resulting insoluble fraction collected by filtration and air dried to yield a 6a-azido-21- oxygenated-4-pregnene-3,20-dione, e.g. fia-azido-prednisone ZI-acetate (i.e. Goa-azido-1,4-pregnadiene-17a,2ldiol-3,11-20-trione ZI-acetate). Purification is usually effected by recrystallization or chromatography.

In our process whereby the novel 6a-azido-21-oxygenated-4-pregnene-3,20-diones and 6a-azido-21-oxygenated-1,4-pregnadiene-3,20diones of Formula I are prepared, the requisite starting steroids are usually 4-pregnene-2l-oxygenated-3,20-diones or the l-dehydro analogs thereof substituted at 0-6 by 6fl-bromo or 6 3-chloro. Alternatively, the substituent at C-6 may be a pseudohalogen such as tosylate or mesylate.

The 0-6 substituted intermediates are prepared from known 6-unsubstituted-3-keto-4-pregnenes. Introduction of the halogeno or pseudohalogeno substituent at 0-6 is carried out by any one of several known methods. For example, allylic halogenation of a 3-keto-4-pregneneor a 3-keto-1,4-pregnadiene with a reagent such as N-bromoacetamide, N-chlorosuccinimide, bromine or chlorine in such solvents as chlorobenzene or dioxane yields the corresponding 6-halogeno 21 oxygenated-4-pregnene-3,20- dione or the l-dehydro analog thereof. Esterificatiou of a 6 hydroxy 21 oxygenated-4-pregnene-3,20-dione or a l-dehydro analog thereof can be made to yield the 6-tosylate or 6-mesylate intermediates.

Prior to introducing a substituent at the '6-position of a 4-pregnene or a 1,4-pregnadiene so as to prepare the 6- halogeno immediate precursor of the compounds of our invention, we prefer to esterify the C-21 hydroxyl group. Thus, for example, in preparing 6;8-bromo-cortisone and 6/3-bromo-16a-methylprednisone for ultimate conversion into 6u-azidocortisone and "6a-azido-16a-methylprednisone, respectively, usually employed as starting compound is a 21-ester of cortisone and 16a-methylprednisone, respectively, e.g. cortisone ZI-acetate and 16a-methylprednisone ZI-acetate, respectively. It is apparent that the Gar-azido-21-oxygenated-4-pregnene-3,20-diones and the 6a-azido-21-oxygenated-1,4-pregnadiene-3,20-diones prepared by our process from the corresponding 6 3-halogeno derivatives will thus contain the original ester protective group at C-21. These ester groups may be conveniently hydrolyzed either chemically or microbiologically by means of Flavobacterium dehydrogenans according to known analogous Procedures. The 60: azido polyhydroxy-4- pregnenes and 1,4-pregnadienes thus obtained may be selectively re-esterified at C2l by methods well known in the art.

This process aspect of our invention whereby a 6,6-substituted (preferably a 65-halogeno)-2l-oxygenated-4- pregnene-3,20-dione upon reaction with an alkali metal azide in a non-reactive organic solvent is converted to the corresponding 6a-azido-4-pregneneis applicable to any steroid containing a 3-keto-4-dehydro-configuration. Thus, any pregnene containing a 3-keto-4-dehydro moiety which will form a 6-substituted derivative such as the 6-halo geno-, 6-tosyloxy-, or 6-mesyloxy-, a requisite starting intermediate, will form the corresponding 6tZ-aZldO compound upon treatment with an alkali-metal azide in a nonreactive organic solvent according to our invention.

GENERAL DESCRIPTION OF PROCESS FOR PRE- PARING 6 AZIDO 21 OXYGENATED 1,4,6- PREGNATRIENE-3,20-DIONES The 6 azido 2l-oxygenated-1,4,6-pregnatriene-3,20- diones of Formula I are prepared from the corresponding 6-azido-21-oxygenated-4,6-pregnadiene 3,20 diones of Formula I by the fourth process aspect of our invention by reaction of said 6-azido-4,6-pregnadiene in an inert solvent (preferably dioxane) with 2,3-dichloro-5,6-dicyanobenzoquinone (hereinafter referred to as DDQ) in the presence of a strong acid (preferably hydrochloric acid) and usually also in the presence of water.

According to our process, a 6-azido-21-oxygenated-4,6- pregnadiene-3,20-dione of Formula I (e.g. 6-azido-4,6- pregnadiene-l7a,21-diol-3,11,20 trione 21 acetate) is treated with an excess (based upon molar ratios) of DDQ in a non-reactive, organic solvent (usually benzene or preferably dioxane) in the presence of a strong acid (e.g. trifluoroacetic, sulfuric or, preferably, hydrochloric acid) advantageously in amounts at least equimolar to the 6- azido-4,6-pregnadiene, and usually also in the presence of water.

The amount of water preferably employed in our process is dependent upon the strong acid catalyst used; with hydrochloric acid as strong acid the presence of from 5% to 10% water in dioxane produces optimum yields when converting 6-azido-4,6-pregnadiene-17a,21- dio1-3,11,20-trions 2l-acetate at 60 C. to the corresponding 6-azido-1,4,6-pregnatriene. When trifiuoroacetic acid is employed as the strong acid, the yields and purity of product obtained are similar whether derived from a reaction mixture containing only a trace of water in dioxane or a reaction mixture containing 10% water in dioxane; however, the reaction rate appears faster with only a trace of water present.

Our reaction is preferably carried out at temperatures in the range of from 60 C. to C. At lower temperatures, the rate of reaction is slower; at higher temperatures, side reactions occur resulting in lower yields of 6- azido-1,4,6-pregnatriene.

Our reaction whereby a 6-azido-4,6-pregnadiene upon treatment with DDQ and a strong acid is converted to a- 6-azido-1,4,6-pregnatriene, is preferably carried out utilizing concentrated hydrochloric acid as the strong acid. We have found that optimum yields of 21-oxygenated-6- azido-1,4,6-pregnatriene-3,20-dione with minimum side reactions are obtained from a 21-oxygenated-6-azido-4,6- pregnadiene-3,20-dione when there is employed from about one to five moles of concentrated hydrochloric acid per mole of steroid and said reaction is carried out at about 60 C. to 80 C. with the aqueous organic solvent being dioxane containing from about to about water and with the concentration of hydrochloric acid and of the steroid in the aqueous dioxane preferably being from about 1% to about 5% by volume.

We have found that when greater or smaller quantities of. acid and/ or water are used than those falling within the preferred range, the yield of 6-azido-l,4,6-pregnatriene diminishes with a concomitant increase of side product formation. Additionally, when the concentration of hydrochloric acid or of 6-azido-4,6-pregnadiene in the aqueous dioxane reaction mixture falls outside the 1% to 5% by volume range, or when high temperatures, e.g. over 100 C., are employed, lower yields of 6-azido-1,4,6- pregnatriene with lesser purity are obtained.

We have found a convenient water-solvent-acid for use in our process to be one containing about 9.0% water in dioxane and about 0.4% hydrochloric acid (i.e. a solution containing 49.5 ml. dioxane, 0.5 ml. concentrated hydrochloric acid an 5 ml. water). Optimum yields of 6- azido1,4,6-pregnatriene are obtained by our DDQ dehydrogenation process when a sufficient quantity of the aforementioned aqueous dioxane-hydrochloric acid is added to a 6-azido-4,6-pregadiene so there is present in the reaction mixture from one to five moles concentrated hydrochloric acid per mole of steroid.

In carrying out the physical embodiment of a preferred method of this process, the reaction mixture comprising a 6-azido-4,6-pregnadiene and hydrochloric acid in aqueous dioxane is usually heated under an inert gas, e.g. nitrogen, at temperatures in the range of from about 60 C. to about 80 C. The dehyldrogenation reaction is usually completed in from 30 minutes to about 2 hours as indicated by the absence of 6-azido-4,6-pregnadiene starting compounds, as determined by thin layer chromatographic techniquesyfor example. The 6-azido- 1,4,6-pregnatriene thereby formed is isolated via conventional techniques such as pouring the reaction mixture into water, extracting with an organic solvent and separating the products utilizing chromatographic techniques.

Our process is advantageously (although not necessarily) carried out in the absence of oxygen. Aqueous hydrochloric acid is preferred as strong acid catalyst although other strong acids such as sulfuric and trifluoroacetic may also be used, usually in the presence of water.

The 6-azido-1,4,6-pregnatrienes of this invention are not easily formed by the usual methods known in the art. Thus, for example, isolatable quantities of 6-azido- 1,4,6-pregnatriene are 'not obtained when the corresponding 6-azido-4,6-pregnadienes are treated in anhydrous dioxane with DDQ alone or with DDQ in the presence of a weak acid such as benzoic acid, or when subjected to the action of microbiological dehydrogenating agents such as Corynebacterium simplexand Bacillus spaericus utilizing conventional techniques. Similarly, treatment of a 6fi-azido-7a-acyloxy-1,4-pregnadiene with a tetraalkylammonium halide according to the first process aspect described hereinabove does not yield isolatable quantities of a 6-azido-1,4,-6-pregnatriene of Formula I. It is thus unexpected and particularly advantageous that treatment of a 6-azido-4,6-pregnadiene of Formula I with DDQ in the presence of a strong acid will yield a 6-azido-1,4,6- pregnatriene of our invention.

PREPARATION OF ESTERS OF OUR INVENTION 6-azido-4-pregnenes of Formula I having ester groups such as at C-l6, C-17, and C-21 can be converted in known manner into 6-azido 4-pregnenes having the hydroxyl groups as, for example, by the action of acidic or alkaline saponification agents. When the 6-azido-4-pregnene of Formula I contains a chlorohydrin or bromohydrin at C-9 and C-11 (i.e. wherein X is halogen and Y is (H,(3OH), we prefer to hydrolyze in a slightly acid medium, e.g. utilizing 70% perchloric acid in methanolchloroform to minimize epoxide formation at C-9 and C-11. When hydrolyzing ester groups of compounds of Formula I not containing a 9(1l)-chlorohydrin or bromohydrin, we usually prefer to use methanolic sodium hydroxide keeping the reaction medium at about 0 C. and under an inert atmosphere, e.g. Argon. If an ester group is present at 0-11, such as in 6a-azido-prednisolone triacetate, it is convenient to convert the esterified compound to the free hydroxy analog by the action of the microorganism Flavobacterium dehydrogenans.

Similarly, alkylidenedioxy functions at C-17 (21) in a 6-azido-4-pregnene of Formula I can be converted in known manner to the corresponding 17,2l-dihydroxy steroid in an acidic medium (e.g. 50% aqueous acetic acid) under an atmosphere of nitrogen.

Compounds of Formula I, prepared in accordance with our invention, which possess a 2l-hydroxyl group, can be converted into pharmacologically acceptable esters utilizing known procedures. When preparing hydrocarbon carboxylic acid esters of hydroxy groups at C-21 and most secondary hydroxy groups such as at C-7 and at 0-16, we prefer to utilize as esterification medium an acid anhydride in pyridine at room temperature, e.g. acetic anhydride, propionic anhydride, valeric anhydride in pyridine. When an ester of an aromatic carboxylic acid is desired, the acyl halide, e.g. benzoyl chloride, toluyl chloride, in pyridine is preferably utilized as esterification agent.

Similarly, procedures known in the art are utilized to convert a 17,2l-dihydroxy compound of our invention, e.g. of Formula I to the corresponding l7-mono-acyl or 17,21-di-acyl derivative, e.g. of Formula I. Thus, 17a,2ldiesters may be prepared by acylation of the corresponding 17a,21-diols or 17a-hydroxy-21-acyloxy compounds. This is preferably effected by reaction of the steroid with an appropriate acid anhydride in the presence of a strong acid catalyst such as, e.g. p-toluenesulfonic acid, perchloric acid or strongly acidic cation exchange resins, or by using trifluoroacetic anhydride with an appropriate lower alkanoic acid. The reaction may be carried out in the absence of a solvent or in a non-polar solvent, e.g. carbon tetrachloride, benzene, toluene, methylene chloride and chloroform. Heating may or may not be necessary according to the reactivity of the reaction components.

When preparing a compound of Formula I having different acyl groups at C-17 and C-21, one may first prepare a 2l-monoester and then esterify the C-21 monoacylate under more forcing conditions to introduce a different acyl group in the 17u-position.

The 17,21-diesters may also be prepared by acylation of the corresponding 21-hydroxy-17u-monoesters by treatment thereof with the appropriate acid anhydride or acid chloride under basic conditions, preferably in the presence of a tertiary organic base, e.g. pyridine, quinoline, N-methylpiperidine, N-methylmorpholine or dimethylanilino. The reaction may be carried out with or without solvents or with or without heat as may be necessary.

The 17-monoesters of our invention may be prepared by hydrolysis of a corresponding 17,21-ortho ester or l7u,2l-diester.

In preparing 17-monoesters via hydrolysis of a 17,21- ortho ester, the 17,21-ortho ester is conveniently prepared by reaction of the 17u,21-diol with an alkylortho ester followed by hydrolysis of the resulting 17,21-ortho ester under mild conditions, i.e. hydrolysis in the presence of an acid catalyst, e.g. a lower alkanoic acid such as acetic or propionic, or a strong mineral acid such as hydrochloric sulfuric acid.

The acyl groups at (3-17 and at 0-21 of the 17-monoacyloxy and 17,2l-diacyloxy-6-azido-4-pregnenes of Formula I may be introduced either before or after the 6- azido function is present in the molecule. It is preferred, however, when preparing 17,21-diacylates of Formula I that the ester groups be present prior to introducing the 6-azido group; whereas esterification at C-17 to produce a l7-1nono-acylate of Formula I is preferably carried out on a 6-azido-17a-hydroxy-4-pregnene of Formula I utilizing techniques known in the art as described hereiuabove.

The novel 20-keto-16a,17a,2 l-trihydroxy compounds of Formula I may be converted to the 16a,17-alkylidenedioxy derivatives utilizing procedures known in the art, e.g. by reacting a l6a,l7a-hydroxy steroid of Formula I (e.g. 6-azido-16a-hydroxy-fi-dehydrocortisone) with a ketone or aldehyde (e.g. acetone, acetylaldehyde) in the presence of a mineral acid (e.g. hydrochloric acid) whereby is obtained the corresponding 16a,l7 x-alkylidenedioxy derivative (e.g. 6-azido-16a,17a-isopropylidenedioxy-4,6- pregnadiene-21-ol-3,l1,20 trione).

Similarly, 17,2l-alkylidenedioxy derivatives of Formula I may be prepared from the corresponding 17,21-dihydroxy-20-keto-derivatives by treatment with a ketone, aldehyde, acetal, or lower alkyl ketal in the presence of a small amount of acid utilizing known techniques. For example, 6-azido-6-dehydrohydrocortisone and 2,2 dimethoxypropane in dimethylformamide in the presence of a catalytic amount of p-toluenesulfonic acid produces 6-azido-17a,2l-isopropylidenedioxy 4,6 pregnadiene- 3,11,20-trione.

The following examples are illustrative of the procedure employed in preparing the compounds of this invention, but are not to be construed as limiting the scope thereof, the scope of our invention being defined only by the appended claims.

PHARMACEUTICAL FORMULATIONS Following are examples of pharmaceutical compositions comprising 6-azido-4,6-pregnadiene-17a,21-diol-3,11, 20-trione 21-acetate which are illustrative of formulations in which the compounds of our invention may be incorporated.

(I) PARENTERAL COMPOSITIONS A. Intramuscular or subcutaneous aqueous suspension Mg./ml.

6 azido 6 dehydrocortisone 21-acetate (sterile,

microcrystalline) 5.0 Monobasic sodium phosphate 3.0 Dibasic sodium phosphate, anhydrous 6.0 Polysorbate 80, USP 0.5 Benzyl alcohol, N.F. 9.0 Methylparaben, USP 1.8 Propylparaben, USP 0.2 Sodium carboxymethylcellulose, USP 5.0 Disodium edetate, USP 0.1

Polyethylene glycol 4000, USP 20.0 Water for injection, USP q.s. ad 1.00 ml.

(B) Intramuscular or subcutaneous oil injection 24 (D) Intravenous infusion Mg./ml. 6-azido-6-dehydrocortisone 21-a'cetate 5.0

Dimethylacetamide q.s. 1.00 ml. I

Note: This infusion is to be diluted with 500 ml. 50% dextrose injection, U.S.P. before administration.

(II) OPHTHALMIC COMPOSITIONS (A) Ointment 6-azido-6-dehydrocortisone 21-acetate (microcrystalline, sterile) Sodium 'sulfacetamide, U.S.P. 100.0

Methylparaben, U.S.P. 0.5 Propylparaben, U.S.P. 0.1 Mineral oil, U.S.P. 179.0 White petrolatum, U.S.P. 715.4

(B) Suspension Mg./ml.

6-azido-6-dehydrocortisone 21-acetate (sterile, mi-

crocrystalline) 5.0 Monobasic sodium phosphate 1.25 Dibasic sodium phosphate, anhydrous 0.26 Sodium chloride, USP 6.4 Triton WR-1339 1.0

Benzalkonium chloride, U.S.P. 0.25

Glyceryl triacetate 880.0 Polyethylene glycol 200 q.s. ad 1.0 g.

(B) Suspension Mg./m1. 6-azido-6-dehydrocortisone 2l-acetate (sterile, mi-

crocrystalline) 5.0 Neomycin sulfate, U.S.P 6.0 Sodium propionate, N.F. 50.0 Polyvinylpyrrolidone (Plasdone K29-32) 30.0 Propionic acid 99% R. 0.0025 ml. Purified water, U.S.P., distilled 1.00 ml.

(C) Solution Mg./ml. 6-azido-6-dehydrocortisone 2l-acetate (sterile, mi-

crocrystalline) 5.0 Cetylpyridinium chloride, N.F 0.2 Glycerin U.S.P. 250.0

Propylene glycol, USP q.s. 1.00 ml- 25 (IV) ORAL COMPOSITIONS (A) Liquid Mg./ml.

6-azido-6-dehydrocortisone ZI-acetate 0.500 Sodium benzoate, U.S.P. 1.000 Citric acid, U.S.P 3.000 Sodium chloride, U.S.P 0.500 Standard granulated sugar, food grade 550.000 Sorbitol solution, U.S.P. 200.000 Propylene glycol, U.S.P 50.000 F.D.C. yellow #5, certified .050 Imitation cherry flavor, Ungerer .010 Terpeneless organic extract, Ungerer .005 Alcohol, U.S.P. 5.000 Purified water, U.S.P. to make 1.000 ml.

MgJTablet 18. Tablets:

5-az1do-6-dehydrocortisone 2l-acetate (micronized) 2. 50 5. Lactose, hydrous, impalpable powder,

U.S.P 81.70 79.00 Pregelatinized corn starch. 0. 5O 0. 50 Corn starch, food grade... 16.00 15. 20 Magnesium stearate, U.S.P.. 0. 30 0. 30

Total weight 7 100.00 100.00

C. Tablets:

6-azido-6-dehydrocort:lsone 21-acetate (mieronized) 2. 30 5. 00 Lactose, hydrous, impalpable powder,

U.S.P 77. 00 74. 50 Polyvinylpyrrolidone (Plasdone K29-32). 5.00 5.00 Sodium lauryl sulfate, U.S.P 5. 00 5. 00 Corn starch, food grade 10. 00 10. 00

' Magnesium stearate, U.S.P"; 0. 50 0. 50

Total weight. 100. 00 100. 00

D. Capsules:

6azido-6-dehydrocortisone ZI-acetate (miccronize 2. 500 5. 00 Lactose, hydrous, impalpable powder,

U. 8.? 212. 000 209. 50 Sodium lauryl sulfate, U.S.P 10. 000 10. 00 Magnesium stearate, U.S.P 0. 500 0. 50

Total 225. 000 225. 00

(V) TOPICAL COMPOSITIONS (A) Ointment Mg./ gm. 6-azido-6 dehydrocortisone 21 acetate (micronized) 5.0 Mineral oil, U.S.P. 50.0 White petrolatum, U.S.P. to make 1.0 g.

(B) Ointment Mg./ gm. 6-azido-6 dehydrocortisone 21 acetate (micronized) 5.0 Stearyl alcohol, U.S.P. 50.0 Polyethylene glycol 400, U.S.P 600.0 Polyethylene glycol 4000, U.S.P. to make 1.0 g.

I (C) Cream Mg./gm. 6-azido-6 dehydrocortisone 21 acetate (micronized) 5.0 Stearyl alcohol, U.S.P. 90.0 White petrolatum, U.S.P 10.0 Propylene glycol, U.S.P. 50.0 Sodium lauryl sulfate, U.S.P. 15.0 4-chloro-m-cresol, pharmaceutical grade 1.0 Purified water, U.S.P. to make 1.0 gm.

26 (D) Cream Mg./gm.

6-azido-6 dehydrocortisone 21 acetate (micronized) 5.0 Stearic acid, U.S.P 60.0 Glyceryl monostearate, cosmetic 100.0 Propylene glycol, U.S.P 50.0 Polyoxyethylene sorbitan monopalmitate, cosmetic 50.0 Sorbitol solution, U.S.P. 30.0 Benzyl alcohol, N.F 10.0 Purified water, U.S.P. to make 1.0 gm.

EXAMPLE 1' -6-azido-4,'6-pregnadiene-17,2l-diol-3,11,20-trione 21- acetate (6-azido-fi-dehydrocortisone 21-acetate) (A) 6p-azido-7a,l7a,21-trihydroxy-4-pregnene- 3,11,20-trione 21-acetate (1) To a solution of 3.7 g. of 6a,7a-epoxy-17a,21- dihydroxy-4-pregnene-3,11,20-trione 21 acetate in 250 ml. dioxane and 600 ml. methanol, add a solution of 12 g. sodium azide in ml. water and 10 m1. acetic acid. Allow the reaction mixture to stand overnight at room temperature then pour in Water and extract the aqueous mixture with chloroform. Dry the combined extracts over magnesium sulfate and evaporate the solvent to a residue comprising 613 azido 7a,17,21-trihydroxy-4-pregnene- 3,11,20-trione 21-acetate; yield 3.9 g. Purify by crystallization from methylene chloride to give 3.04 g. of 6B- azido-7a,l7a,21 trihydroxy-4-pregnene-3,l1,20-t1ione 21- acetate.

[a] +123 (dioxane) M3,??? 231 mp (e=12,975)

(2) Alternatively the compound of this example is prepared as follows. To a solution of 200 mg. of Se m-epoxy- 17u,21-dihydroxy-4-pregnene-3,11,20-trione 21-acetate in 40 ml. of methanol, add 400 mg. of sodium azide and a solution of 40 mg. boric acid in 5 ml. of water. Stir the mixture at 50 C. for 35 minutes, add 100 m1. of water, then extract with chloroform. Wash the combined chloroform extracts with water, dry over magnesium sulfate, then concentrate in vacuo to a residue comprising 613- azido-7a,17a,21-trihydroxy-4-pregnene 3,11,20 trione ZI-acetate which can be utilized without further purification in esterification procedure (1)(B) immediately following.

(B) 6B-azido-7a,l7a-2l-trihydroxy-4-pregnene-3,1 1,20- trione 7,21-diacetate Add 14 ml. of acetic anhydride to a solution of 3.04 g. of 6B azido 7a,17a,21-trihydroxy-4-pregnene-3,11,20- trione ZI-acetate in 30 ml. of pyridine and allow the reaction mixture to stand at room temperature for 18 hours. Pour the reaction mixture into 400 ml. of water and stir for 20 minutes. Collect the insoluble fraction by filtration and dry in vacuo to yield 3.031 g. of product comprising 6fl-azido-7a, 17a,2l-trihydroxy-4-pregnene-3, 1 1,20- trione 7,21-diacetate.

[a] +89.2 (dioxane); A251? 229 mu (e=12,470)

(C) 6-azido-17u-21-dihydroxy-4,6-pregnadiene- 3,11,20-tri0ne 2l-acetate (1) Add 1 g. of 6p azido 7u,17a,21 trihydroxy 4- pregnene 3,11,20 trione 7,21 diacetate to a suspension of 1g. of tetramethylammonium fluoride in 100 ml. of acetonitrile. Allow the reaction mixture to stand at 60 C. for 35 minutes then distill the solvent in vacuo and dissolve the resultant residue in chloroform and pour the chloroform solution into water. Separate the aqueous layer from the organic solution layer and wash the organic solution with aqueous sodium bicarbonate. Dry the organic solution over magnesium sulfate and evaporate the solvent under a steam of nitrogen to obtain a residue comprising 6 azido :,21 dihydroxy 4,6 pregnadiene-3,l1,20-trione 21-acetate. Purify by crystallization in methanol and filtration of the resultant crystallized product to obtain 511 mg. of 6 azido 1711,21 dihydroxy 4,6 pregnadiene 3,11,20 trione 21 acetate which crystallizes with a mole of water as solvent.

[a]D+300.7 250 e=13176); Agzihennl my Calcd. for C23H27O6N3'H2O: N2=9.15%. Found: N2 =9.07%.

(2) Alternatively, above procedure 1(C)(1) may be carried out at room temperature for 18 hours (rather than at 60 C. for 35 minutes) and there is formed 6- azido 1701,21 dihydroxy 4,6 pregnadiene 3,11,20- trione 21-acetate.

(3) Alternatively, the compound of this example is prepared as follows. Dissolve 4 g. of tetramethylammonium fluoride pentahydrate in 200 ml. of acetonitrile and evaporate in vacuo to a residue. Repeat this procedure once again. To the resulting dry residue comprising tetramethylammonium fluoride add 2 g. of 6 8 azido 711,170;- 21 trihydroxy 4 pregnene 3,11,20 trione 7,21 diacetate in 100 ml. of acetonitrile. Stir the reaction mixture under an atmosphere of argon at 25 C. for two hours. Distill the solvent in vacuo to a residue comprising 6 azido 1711,21 dihydroxy 4,6 pregnadiene-3,11, 20 trione 21 acetate. Purify by chromatographing on Florisil (pre-washed with hexane) eluting the product with acetone. Evaporate the combined eluates, then crystallize the resultant residue with methanol, to obtain 6- azido 1701,21 dihydroxy 4,6 pregnadiene 3,11,20- trione 21-acetate (i.e. 6-azido 6 dehydrocortisone 21- acetate).

(4) Alternatively the compound of this example is prepared utilizing tetramethylammonium fluoride pentahydrate rather than with anhydrous tetramethylammonium fluoride in a manner such as the following. Add 2 g. of tetramethylammonium fluoride pentahyddate to 200 ml. of acetonitrile and heat the mixture with stirring until the tetramethylammonium fluoride pentahydrate liquifies. Cool to 25 C. under an atmosphere of nitrogen then add 2 g. of 613 azido 7ot,l7a,2l trihydroxy-4-pregnene- 3,11,20-trione 7,21-diacetate and stir the reaction mixture under an atmosphere of nitrogen at 25 C. for three hours. Concentrate the reaction mixture to about 100 ml. in vacuo at 25 C. then pour into 1 liter of water and extract the aqueous mixture with 10 100 ml. portions of dichloromethane. Wash the combined dichloromethane extracts with 2 50 ml. portions of water, dry the dichloromethane over magnesium sulfate then evaporate in vacuo to a residue, triturate the residue with about 25 ml. of boiling ether, cool to 20 C. and filter the solid fraction comprising 6 azido 1711,21 dihydroxy-4,6-pregnadiene 3,11,20 trione 21 acetate. Purify by crystallization in methanol to obtain 6 azido 701,21 dihydroxy 4,6 pregnadiene 3,11,20 trione 21 acetate which crystallizes with a mole of water as solvent:

[@ 300.7" (dioxane).

Alternatively, the compound of this example is prepared from 65 azido 7a,17oz,21 trihydroxy 4 pregnene 3,11,20 trione 21 acetate (compound of Example 1(A) according to the following procedures (D) and (E) (D) 6,8-azido-7u, 17 (1,2 l-trihydroxy-4-pregnene-3,1 1,20-

trione 7-methanesulfonate 21-acetate To a solution of 3g. of 6 3-azido-7a,17a,21-trihydroxy- 4-pregnene-3,11,20-trion 21-acetate in 30 ml. of pyridine add 1.5 ml. of methanesulfonyl chloride and allow the reaction mixture to stand at room temperature for 17 hours. Pour the reaction mixture into water and collect by filtration the resultant precipitate comprising 6fl-azido-7a,l7a, 21-trihydroxy-4-pregnene-3,l1,20 trione 7 methanesulfonate 21-acetate. Purify by drying the precipitate in vacuo and crystallizing from ether.

mcthnnol max.

In the above procedure, by utlizing 2.2 ml. of ptoluenesulfonyl chloride in place of the 1.5 ml. of methanesulfonyl chloride there is obtained the corresponding 7-p-toluenesulfonate ester, i.e. 6fi-azido-7a,17a,2l-trihydroxy-4-pregnene-3,l1,20-trione 7-p-toluenesulfonate 21- acetate.

(E) 6-azido-4,6-pregnadiene-17a,21-diol-3,11,20-trione 21-acetate Add 1.5 g. of 6B azido 7a,17a,21 trihydroxy-4- pregnene-3,1l,20-trione 7-methanesulfonate 21-acetate to a suspension of 0.750 g. of tetramethylammonium fluoride in 150 ml. acetonitrile. Warm the reaction mixture at 60 C. for 35 minutes then remove the solvent in vacuo. Dissolve the resultant residue in chloroform and pour into water. Separate the solvent layers and wash the organic layer with aqueous sodium bicarbonate, then dry the organic layer over magnesium sulfate and evaporate the solvent to a residue comprising 6-azido-4,6-pregnadiene- 17u,21-diol-3,11,20-trione 21-acetate. Purify by separation on preparative silica gel plates. Further purify by crystallizing the isolated product with methanol to obtain 6- azido 4,6 pregnadiene- 17a,21-diol-3,11,20-trione 21- acetate.

Similarly, treat 65 azido 7u,17a,2l-trihydroxy-4- pregnene 3,11,20 trione 7-p-toluenesulfonate 2-acetate with tetramethylammonium fluoride in acetonitrile in the above described manner to obtain 6-azido-4,6-pregnadiene-17a,21-diol-3,11,20-trinone 21-acetate.

EXAMPLE 2 6p Azido 4,6-Pregnadiene-1lfl,17u,21-Trio1-3,20-Dione 21 Acetate (6 Azido--Dehydro-Hydrocortisone 21- Acetate) (A) 6a,7a-oxido-1l/3,17u,21-trihydroxy-4-pregnene-3,20- dione 2l-acetate (1) To a solution of 2 g. of 11fi,17a,21-trihydroxy-4, 6-pregnadiene-3,20-dione 21-acetate in 75 ml. of acetone add 2 g. of m-chloroperbenzoic acid over a period of 2.5 hours. Heat the reaction mixture at reflux temperature for five hours, distill the solvent, dissolve the resultant residue in methylene chloride and pour the methylene chloride solution into water. Separate the aqueous layer from the organic solution, wash the organic solution with 200 ml. of 0.2 N-sodium hydroxide. Dry the organic solution over magnesium sulfate and remove the solvent in vacuo to a residue comprising 6a,7a-epoxy-11B,17u,21-trihydroXy-4- pregnene-3,20-dione 21-acetate. Purify by dissolving in methylene chloride and separating via preparative thin layer chromatography to obtain 460 mg. of 6 t,7at-oxidol1fl,17a,21 trihydroxy-4-pregnene-3,20-dione 21-acetate which is used without further purification in the following Example 2(B).

-(2) Alternatively the compound of this example is prepared by treating l1p,17a,21-trihydroxy-4,6-pregnadiene- 3,20-dione 21-acetate (7 g.) with monoperphthalic acid (2.7 g.) in chloroform (700 ml.) at room temperature for 60 hours and isolating the resultant product by washing the chloroform solution successively with aqueous sodium bicarbonate, water, ferrous sulfate solution and again with water. Dry the chloroform solution over magnesium sulfate and distill thesolvent to a residue comprising 6a,7aoxido 11B,171:,2l-trihydroxy-4-pregnene-3,20-dione 21- acetate. Purify by crystallization from acetone, M.P. 270 C.

(3) Alternatively, the compound of this example is prepared according to procedure 2(A)(1) but using as solvent ml. of methylene chloride/tert.-butanol (1:1) (rather than acetone) and carrying out the reaction at reflux temperature for hours to obtain 6u,7u oxido-11fi,17u,21-trihydroxy-4-pregnene-3,ZO-dione 21-acetate.

(B) 6,8-azido-7a,1 lfi,17a,21-tetrahydroxy-4-pregnene- 3,20-dione 21-acetate To a solution of 450 mg. of 6m,7ot-0XidO-11B,l7oz,2ltrihydroxy-4-pregnene-3,20-dione 2l-acetate in 20 ml. of

dioxane and 60 ml. of methanol add a solution of 1.3 g. sodium azide in ml. water and 1 ml. acetic acid. Allow the reaction mixture to stand at room temperature for 6 days then pour the reaction mixture into water and extract with chloroform. Dry the chloroform solution over magnesium sulfate and evaporate the solvent to a residue comprising 68 azido-7u,11/8,17a,21-tetrahydroxy-4-pregnene-3,20-dione 21-acetate. Purify by dissolving in methylene chloride and separating via thick layer chromatography to obtain 250 mg. of 6 3-azido-7a,11p,17a,21-tetrahydroxy-4-pregnene-3,20-dione 21-acetate which is used without further purification in the following Example 2(C).

(C) 6B-azido-7a,11B,17a,21-tetrahydroxy-4-pregnene- 3,20-dione 7,2l-diacetate In a manner similar to that described in Example 1(B), treat 6,8 azido-7a,115,170:,21-tetrahydroxy-4-pregnene-3, -dione ZI-acetate with acetic anhydride in pyridine at room temperature for 24 hours. Isolate the resultant product in a manner similar to that described in Example 1(B) to obtain 6/3 azido-7a,l1/3,17a,21-tetrahydroxy-4-pregnene-3,20-dione 7,21-diacetate.

(D) 6-azido-llfl,1701,21-trihydroxy-4,6-pregnadiene- 3,20-dione ZI-acetate To a solution of 300 mg. tetramethylammonium fluoride in 15 ml. acetonitrile add a solution of 150 mg. of 6B azido 7a,l113,17a,21-tetrahydroxy-4-pregnene-3,20- dione 7,2l-diacetate in 15 ml. of acetonitrile. Allow the reaction mixture to stand at 60 C. for 40 minutes then remove the solvent in vacuo, dissolve the resultant residue in methylene chloride, pour the methylene chloride solution into water, separate the aqueous layer from the organic layer and wash the organic layer in aqueous sodium bicarbonate solution. Dry the organic layer over magnesium sulfate and remove the solvent in vacuo to a residue comprising 6 azido-l1/3,17a,2l-trihydroxy-4,6-pregnadiene-3,20-dione 2l-acetate. Purify via preparative thin layer chromatography utilizing silica gel to obtain 65 mg. of 6 azido 11B,17u,21 trihydroxy-4,6-pregnadiene-3,20- dione 21-acetate,

me 351 mp. (.=12,452 A332 299 mp (e -12,452); a (CD013), 0.73, 1.31, 2.15, 3.38, 4.66, 5.13, 5.78, 6.12 p.p.m.

EXAMPLE 3 6-azido-4,6-pregnadiene-17a,2 l-diol-3,20-dione 21-acetate (A) 6 8 azido-7u,17u,2l-trihydroxy-4-pregnene-3,20- dione 21-acetate.--In a manner similar to that described in Example 1(A)(1) treat a solution of 6u,7a-epoxy-4-pregnene 17a,21-diol-3,20-dione 2l-acetate in dioxane and methanol with a solution of sodium azide in dilute acetic acid. Isolate andpurify the resultant product in a manner similar to that described to obtain 6fl-aZid0-7oz,17u,2l-trihydroxy-4-pregnene-3,20-dione ZI-acetate.

(B) 6,8 azido-7a,17a,2l-trihydroxy-4-pregnene-3,20- dione 7,21-diacetate.-In a manner similar to that described in Example 1(B), treat 6fl-azido-7a,l7a,2l-trihydride in pyridine at room temperature. Isolate and purify droxy 4-.pregnene-3,20-dione ZI-acetate with acetic anhythe resultant product in a manner similar to that described in-Example 1(B) to obtain 6B-azido-7a,l7a,21-trihydroxy- 4-pregnene-3,20dione 7,21-diacetate.

(C) 6-azido-4,6-pregnadiene-17a,21-diol-3,20-dione 21- acetate.-In a manner similar to that described in Example 1(C)(1) treat 65 azido-7a,17oe,21-t1ihydroxy-4-pregnene 3,20 dione 7,2l-diacetate with tetramethylammonium fluoride in acetonitrile. Isolate and purify the resultant product in a manner similar to that described in Example 1(C)(1) to obtain '6-azido-4,6-pregnadiene-17a, 21-diol-3,20-dione 21-acetate.

30 EXAMPLE 4 6-azido-4,6-pregnadiene-21-ol-3 ,ZO-dione 2 l-acetate (A) 6u,7woxido-4-pregnene-2l-ol-3,20-dione 21 acetate.-In a manner similar to that described in Example 2(A) (I) treat 4,6-pregnadiene-21-ol-3,20-dione 21-acetate with m-chloroperbenzoic acid in acetone at reflux temperature. Isolate and purify the resultant product in a manner similar to that described to obtain 6u,7a-oxido-4-pregnene- 21-o1-3,20-dione 21-acetate.

(B) 6B-azido-7u,21-dihydroxy-4-pregnene-3,20-dione 2lacetate.Treat 6oz,70c-OXid0-4-pr6gl1ene-21-0l-3,20 dione Zl-acetate with sodium azide in dilute acetic acid in a manner similar to that described in Example 1(A) (1). Isolate and purify the resultant product in a manner similar to that described to obtain 6fi-azido-7a,21-dihydroxy-4- pregnene-3,20-dione 2l-acetate.

(C) 6B-azido-7a,21dihydroxy-4-pregnene-3,20-dione 7, 2l-diacetate.-Treat 6/3-azido-7u,21-dihydroxy 4 pregnene-3,20-dione 21-acetate with acetic anhydride in pyridine at room temperature in a manner similar to that described in Example l( B). Isolate and purify the resultant product in a manner similar to that described to obtain 6B'-azido-7a,2l-dihydroxy-4-pregnene-3,ZO-dione 7,21 diacetate.

(D) 6-azido-4,6-pregnadiene-2l-ol-3,20-di0ne 2l-acetate.Treat 6,8-azido-7u,21-dihydroxy-4-pregnene 3,20- dione 7,21-diacetate with tetramethylammonium fluoride in acetonitrile at 60 C. in a manner similar to that described in Example 1(C)(1). Isolate and purify the resultant product in a manner similar to that described to obtain 6-azido-4,6-pregnadiene-21-ol-3,20-dione 21-acetate.

EXAMPLE 5 6/3-azido-7a,17a,21-trihydroxy-4,9 l l -pregnadiene-3,20- dione 7,21-diacetate (A) 6/8-azido-7a,1 1a,17a,21-tetrahydroxy-4-pregnene-3, 20-dione ll-p-toluenesulfonate 21-acetate.In a manner similar to that described in Example 1(A) (1) treat 600,70:- oxido-l1a,17a,21-trihydroxy-4-pregnene-3,20-dione 1 l-ptoluenesulfonate 2l-acetate with sodium azide in dilute acetic acid at room temperature. Isolate and purify the resultant product in a manner similar to that described in Example 1(A)(1) to obtain 65-azido-7u,11a,17a,21-tetrahydroxy-4 pregnene-3,ZO-dione ll-p-toluenesulfonate 2lacetate.

(B) 6fl-azido-7a,11a,17a,21-tetrahydroxy-4-pregnene-3, 20-dione 7,2l-diacetate 11-p-toluenesulfonate.-In a manner similar to that described in Example 1(B) treat 63- azido-7m,l1a,17,21-tetrahydroxy-4-pregnene-3,20 dione ll-p-tolnenesulfonate 21-acetate with acetic anhydride in pyridine. Isolate and purify the resultant product in a manner similar to that described in Example 1(B) to obtain 6fl-a'zido-7a,11a,l7a,21-tetrahydroxy-4 pregnene 3,20- dione 7,2l-diacetate ll-p-toluenesulfonate.

(C) 6fi-azido-7a,17a,21-trihydroxy 4,9(11) pregnadiene-3,20-dione 7,21-diacetate.-To a solution of 1.9 g. of anhydrous sodium acetate in 20 ml. of acetic acid at about C. and 1 g. of 6/3-azido-7a,11a,17a,2l-tetrahydroxy- 4-pregnene-3,20-dione 7,2l-diacetate ll-p-toluenesulfonate. Heat the solution at reflux temperature for 40 minutes then chill in ice and dilute with cold water. Separate the resultant precipitate by filtration, wash with Water, dry and crystallize from acetone-hexane to give 6fi-azido-7u, 17a,21-trihydroxy-4,9(1l)-pregnadiene-3,20 dione 7,21- diacetate.

EXAMPLE 6 6-azido-9u,1 1 ,B-dichloro-4,6-pregnadiene- 17 oz,21di01-3 .20-

dione ZI-acetate (A) 6fl-azido-7u,17u,21-trihydroxy-9a,1IB-dichloro 4- pregnene-3,20-dione 7,21-diacetate.--To 1.0 g. of 6,8- azido-7a,17a,21-trihydroxy-4,9 1 1 -pregnadiene 7,21-diacetate dissolved in 35 ml. of carbon tetrachloride at 20 C. add 2.1 ml. chlorine gas in carbon tetrachloride (65 mg. Cl /ml.) and 0.15 ml. of pyridine. Stir the reaction mixture at 20 C. for 20 minutes then allow the reaction mixture to warm to room temperature over 40 minutes. Filter the reaction mixture and concentrate the filtrate in vacuo to a residue comprising 6;8-azido-7w,17a,2l-trihydroxy-9a,1 1B-dichloro-4-pregnene-3,20-dione 7,21-diacetate.

(B) 6-azido-9a,1113-dichloro-4,6-pregnadiene 1704,21- diol-3,20-dione 21-acetate.In a manner similar to that described in Example l(C) (2) treat 6,8-azido-7,17a,21- trihydroxy-9a,1 1/3-dichloro-4-pregnene-3 ,20-dione 7,21-diacetate with tetramethylammonium fluoride in acetonitrile at room temperature. Isolate and purify the resultant product in a manner similar to that described in Example l(C) (2) to obtain 6-azido-9a,11fl-dichloro-4,6-pregnadiene-17a,21-diol-3,20-dione 21-acetate.

EXAMPLE 7 6-azido-9a-bromo-11B-fluoro-4,6-pregnadiene-17a,21-di0l- 3,20-dione 21-acetate (A) 6B-azido-7a,17a,21-trihydroxy-9u bromo 115- fluoro-4-pregnene-3,20-dione 7,2l-diacetate.-To a solution of 1.76 g. of 6,8-azido-7a,17a,21-trihydroxy-4,9(11)- pregnadiene-3,20-dione 7,21-diacetate and 0.5 g. of N- bromoacetamide in 50 ml. of diethyl acetic acid, at room temperature add a solution of 0.5 g. of hydrogen fluoride in 4.7 ml. of a chloroform-tetrahyrofuran mixture (1:2). Stir the solution at room temperature for 2 hours then pour into ice water with stirring. Bring the reaction mixture to neutrality by adding sodium bicarbonate then decant the aqueous solution from the resultant precipitate which comprises 613-azido-7a,17u,2l-trihydroxy-9a-bromo- 1lB-fiuoro-4-pregnene-3,20-dione 7,21-diacetate. Purify by dissolving the dried precipitate in acetone-ether and filtering through a column of florisil in ether and eluting the column with acetone-ether. Combine the like acetone-ether eluates and evaporate to a residue. Crystallize the residue from methylene chloride in hexane to give 6B-azido-7a, 17u,2l-trihydroxy-9a-bromo-1lfi-fiuoro 4 pregnene-3, 20-dione 7,21-diacetate.

(B) 6-azido-9a-bromo-1lp-fluoro-4,6-pregnadiene-17a, 2l-diol-3,20-dione 21-acetate.In a manner similar to that described in Example 1(C)(2) treat 6fi-azido-7u, 170:,21 trihydroxy-9a-bromo-llfl-fiuoro-4-pregnene-3,20- dione 7,21-diacetate with tetramethylammonium fluoride in acetonitrile. Isolate and purify the resultant product in a manner similar to that described in Example 1(C)(2) to obtain 6-azido-9a-bromo-llfl-fluoro-4,6-pregnadiene- 17u,21-diol-3,20-dione 2l-acetate.

6-azido-9a-chloro-1 1p-fluoro-4,6-pregnadiene-17a, 21-diol-3,20dione 21-acetate (A) 6fl-azido-7a, 17a,2 1-trihydroxy-9u-chloro-1 lfl-fluoro-4-pregnene-3,20-dione 7,2l-diacetate.--To 0.8 g. of 65- aZidO-7oz,17oc,21 trihydroxy 4,9(11)-pregnadiene-3,20- dione 7,2l-diacetate in 25 ml. of diethylacetic acid add 0.24 g. of N-chlorosuccinimide followed by a solution of 650 mg. of hydrogen fluoride in 3.4 ml. of a tetrahydrofuran-chloroform mixture (1:2). Stir the reaction mixture at room temperature for 46 hours then pour into dilute aqueous sodium carbonate solution. Extract the reaction mixture with methylene chloride and evaporate the combined organic extracts to a residue. Dissolve the residue in acetone-ether and chromatograph on silica gel eluting with acetone-ether. Combine the like eluates and evaporate in vacuo to a residue comprising 6flaZidO-7a,17oc,21- trihydroxy-9a-chloro-1lfi-fluoro 4-pregnene-3,20-dione 7,21-diacetate. Purify by crystallization from acetonehexane.

32 EXAMPLE 9 6,3-azido 7ot,11,8,17a,21 tetrahydroxy c fluoro-4- pregnene 3,20-dione 7,21-diacetate (6 8-azido-7aacetoxy-9a-fluoro hydrocortisone 2-acetate) (A) 6a,7a-oxido-9a-fluoro-4-pregnene-1 1fi,17a,21-t1i01- 3,20-dione 21-acetate.--In a manner similar to that described in Example 2(A)( 1) treat 9m-fluoro-4,6-pregnadiene-11 3,17a,21-triol-3,20-dione 2l-acetate with m-chloroperbenzoic acid in acetone. Isolate the resultant prod uct in a manner similar to that described to obtain 6a,7aoxido-9a-fluoro-4-pregnene 11fi,17a,21 triol-3,20-dione 21-acetate.

Alternatively in a manner similar to that described in the second paragraph of Example 2(A), treat 9u-fluoro- 4,6-pregnadiene-11p,17a,21 triol-3,20-dione 2l-acetate with monoperphthalic acid in chloroform at room temperature to obtain 6u,7a-oxido-9a-fluoro-4-pregnene-11,6, 17a,21-triol-3,20-dione 21-acetate.

(B) 6,B-azido7 0L,1113,17a,21 tetrahydroxy-9u-fluoro-4- pregnene-3,20 dione 21-acetate (6fl-azido-9a-fluoro-4- pregnene-7a,115,17u,21-tetraol-3,20-dione 21-acetate) In a manner similar to that described in Example 1(A)(1) treat 6a,7a-oxido-9m-fluoro-4-pregnene-11fi,17a,21-triol-3, 20-dione ZI-acetate with sodium azide in aqueous methanol. Isolate and purify the resultant product in a manner similar to that described in Example 1(A)(1) to obtain 6p-azido-7a,11p,17a,21 tetrahydroxy 9m-fluoro-4- pregnene-3,20-dione 21-acetate.

(C) 6,8-azido-7u,11B,17,21-tetrahydroxy-9a-fluoro-4- pregnene-3,20-dione 7,2l-diacetate.1n a manner similar to that described in Example l(B) treat 6fl-azido-7a,11fi, 17a,21-tetrahydroxy-9a'fluoro-4-pregnene-3,20-dione 21- acetate with acetic anhydride in pyridine at room temperature. Isolate and purify the resultant product in a manner similar to that described to obtain 6B-flZidO-7a,1lfi,17ot, 2l-tetrahydroxy-9a-fluoro-4-pregnene-3,20-dione 7,21-diacetate.

Alternatively the compound of this example is also prepared according to the following procedures (D), (E), and (F).

(D) 6B-azido-7u,1113,17u,21-tetrahydroxy-9u-bromo-4- pregnene-3,20-dione 7,21-diacetate (6p-azido-7a-acetoxy- 9a-bromo-hydrocortisone 21-acetate).-To a mixture of 0.24 g. of 6fl-azido-7a,17u,21-trihydroxy-4,9(11)-pregnadiene-3,20-dione 7,2l-diacetate in 20 ml. of dioxane (which has been purified by refluxing over sodium followed by distillation) and 2 ml. of water, add 0.07 g. of N-bromoacetamide and 1 ml. of 1.5 N-perchloric acid. Allow the mixture to stand for 2 hours then add a solu-. tion of 0.2 g. of sodium sulfite in 2 ml. of water. Bxtract the reaction mixture with methylene chloride and wash the combined organic extracts with water then dry ovre magnesium sulfate and evaporate to a residue comprising 6B-azido-7a,1lfi,17a,21-tetrahydroxy-9a-br0mo-4- pregnene-3,20-dione 7,21-diacetate. Purify by crystallization from acetone.

(E) 6B-aZidO-7a,17oc,21 trihydroxy 95,11fl-oxido-4 pregnene-3,20-dione 7,2l-diacetate.--To 0.25 g. of 6B- azido-7a,11 8,17a,21-tetrahydroxy 9a-bromo-4-pregnene- 3,20-dione 7,21-diacetate in 30 ml. of acetone add 0.3 g. of potassium acetate. Heat the reaction mixture at reflux temperature for 6 hours then distill the acetone and add water to the resultant residue. Filter the solid which separates and crystallize the solid from methanol-water to give 6B-azido-7a,17,21-trihydroxy 9,8,11,8-oxido-4- pregnene-3,20-dione 7,21-diacetate.

(F) 6B-azido-7a,1l/3,17a,21 tetrahydroxy-9a-fluoro-4- pregnene-3,20-dione 7,21-diacetate.-To 3.5 g. of hydrogen fluoride in 20 ml. of chloroform and 0.6 ml. of tetrahydrofuran at -l0 C. add 1.0 g. of 6B-aZid0-7oc,17oc,21- trihydroxy-9,3,115-oxido 4-pregnene-3,20-dione 7,21-diacetate. Keep the reaction mixture at 10 C. for 3 hours, then pour into aqueous sodium carbonate solution. Separate the organic solvent layer from the water and 33 evaporate the organic solvent to a residue comprising 6B-aZid0-7a,11fl,17u,21 tetrahydroxy-9u fluoro-4'pregnene-3,20-dione 7,2l-diacetate. Purify by crystallization from methanol.

In a similar manner the 9a-chloro analog of the 90:- fiuoro derivative of Example 9(F) is prepared as described in the following Example 9(6).

(G) 6fl-azido -7a,11 3,17u,21-tetrahydroxy 9a chloro- 4-pregnene-3,20-dione'7,21-diacetate5- -Dissolve 0.2 g. of 6/3-azido-7u,l7a,21-trihydroxy-9fl,1IB-oxido 4 pregnene-3,20-'dione 7,21-diacetate in 30 ml. of alcohol-free chloroform and cool the solution to C. Saturate the solution at 0 C.'with anhydrous hydrogen chloride and allow the reaction mixture to stand for 6 hours at 0 C. Distill the solvent in vacuo to a residue comprising 6 3- aZidO-7a,1lfl,17a,2l-tCttahYdlOXY-9a-chl0l'0 4 pregnene-3,20-dione 7,2l-diacetate. Purify byrcrystallization from acetone. v

EXAMPLE 6-azido-9a-halogeno 4,6 pregnadiene-llfl,17ix,21-triol- 3,20-dione 2l acetate (6-azido-9a-halogeno-G-dehydrohydrocortisone ZI-acetate) y In a manner similar to that described in Example 1 (2) treat each of a 6 fl-azido-h, l 1/3,17a,21-tetrahydroxy-9'u-fluoro-4- pregnene-3,20-dione,2l-diacetate,

6p-azido-7u,1 1B,17u,21-tetrahydroxy-9u-chloro-4- pregnene-3,20-dione 7,2l-diacetate, and

6fl-azido-7'a, 1 1 9, 1711,21-tetrahydroxy-9a-bromo-4- pregnene-3,20-dione 7,2l-diacetate with tetramethylammonium fluoride in acetonitrile. Isolate and purify the resultant respective products in a manner similar to that described in Example 1(C) (2) to obtain respectively,

EXAMPLE 11 6-azido-9'a-halogeno e 4,6 pregnadiene l7ct,21-diol 3,11, ZO-Trione 21-Acetate (6-Azido-9ot-Halogeno-6-Deh yrocortisone 2l-acetate) In a manner similar to that described in Example 2(A) l treat -9a-fluoro-4,6-pregnadiene-17a,21-diol-3,1 1,20- trione-21-acetate with m-chloroperbenzoic acid in acetone at reflux temperature. Isolate and purify the resultant product in a manner similar to that described to obtain 6a,7u-oxido-9a-halogeno-4,G-pregnadiene-17a,2ldiol-3,11,20-trione 2.1-acetate.

Alternatively the compound of this example is prepared in a manner similar to that described in Example 2(A) (2), Le. by treating 9a-fluoro-4,6-pregnadiene-17a, 21-diol-3,11,20-trione 21 acetone with excess monoperphthalicacid in chloroform at room temperature for 60 hours; Isolate and purify the resultant product in a manner similar to that described in Example 2(A) (1) to obtain 6a,7u-oxido-9'a-fluoro-4-pregnene 17 ,2 1-diol-3,1 1,20- trione ZI-acetate.

(B) 6fl-azido-7a,17a,21-triol-9e-fluoro-4-pregneney 3,11,20-trione 21-acetate- In a manner similar to that described in Example 1 (A), treat a solution of 6u,7a-oxid0-9 ot-fluoro-4-pregnene-17a, 21-diol- 3,11,20-trione ZI-acetate in dioxane and methanol with a solution of sodium azide in dilute acetate acid. Isolate and purify the resultant product in a manner similar to that described to obtain 6fl-azido-7a,17a,21- triol-9a-fiuoro-4-pregnene-3,11,20-trione 21-acetate.

(C) 6B-azido-7a,l7a,2l-triol-9a-fiuoro-4-pregnene- 3,11,20-trione 7,2l-diacetate (1) In a manner similar to that described in Example 1(B) treat 6p-azido-7a,l7a,2l-trihydroxy c fluoro-4- pregnene-3,l1,20-trione 2l-acetate with acetic anhydride in pyridine. Isolate and purify the resultant product in a manner similar to that described in Example 1(C) to obtain 6fl-azido-7a,17a,21-t1ihydroxy-9u-fluoro-4-pregnene- 3,11,20-trione 7,21-diacetate.

(2) Alternatively the compound of this example is prepared as follows:

To 0.5 g. of 6p-azido-7a,l1/3,17a,21-tetrahydroxy-9afluoro-4-pregnene-3,20-dione 7,21-diacetate in 15 ml. of acetic acid add a solution of 60 mg. of chromium trioxide in 1 ml. of water and 3 m1. acetic acid. Allow the mixture to stand at room temperature for 6 hours then add water and extract the mixture with methylene chloride. Wash the combined organic extracts with 'water, dry over magnesium sulfate, filter and evaporate to a residue comprising 6fi-aZidO-7'et,17a,21-I.I'i0lot-flllOIO-4-Pl6gl16flfi- 3,11,20-1trione 7,21-diacetate. Purify by crystallization from methanol.

(D) -6;3-azido-7a,17a,21-trihydroxy-9a-chloro-4- pregnene-3,11,20-trione 7,2l-diacetate 6fl-azido-7u,l7a,2l-trihydroxy-9'a-bromo 4 pregnene- 3,11,20-trione 7,21-diacetate.--In a manner similar to that described in Example 11(C) (2) treat each of GB-azido- 7a,l1,8,l7a,2l-tetrahydroxy-9'u-chloro 4 pregnene-3, 20-dione 7,21-diacetate and 6fl-azido-7a,1lB,17u,21-tetrahydroxy-9u-bromo-4-pregnene-3,ZO dione 7,21 diacetate with chromium trioxide in aqueous acetic acid. Isolate and purify the resultant products in a manner similar to that described in Example 11(0) (2) to obtain, respectively,

613-azido-7a,17u,21-trihydroxy-9u-chloro-4-pregnene- 3,11,20-trione 7,2l-diacetate and 6p-azido-7 a,17a,2l-trihydroxy-9a-bromo-4-pregnene- 3,11,20 -trione 7,21-diacetate.

(E) 6-azido-9a-halogeno-4,6-pregnadiene-17,2l-di0l- 3,11,20-trione Zl-acetate In a manner similar to that described in Example 1(0) (2.) treat each of 6/8-azido-7a,l7u,2l-trihydroxy-9ufluoro-4-pregnene-3,11,20-trione 7,21 diacetate, 6B- azido-7u,l7a,21-trihydroxy-9a-chloro 4 pregnene-3,1l, 20-trione 7,2l-diacetate and 6fl-azido-7u,17u,21-trihydroxy-9ct-bromo-4-pregnene-3,11,20-trione 7,21-diacetate with tetramethylammonium fluoride in acetonitrile. Isolate and purify the resultant products in a manner similar to that described in Example 1(C) (2) to obtain respectively,

6-azido-9a-fluoro-4,G-pregnadiene-17'a,21-diol-3,1 1,20-

trione 21-acetate,

6-azido-9 a-chloro-4,6-pregnadiene- 17a,21-di0l-3, 1 1,20-

trione Ill-acetate, and

6-azido-9a-bromo-4,6-pregnadiene-l7a,21-diol-3,1 1,20

trione 21-acetate.

EXAMPLE l2.

11-Substituted-6-Azido-lfi-Lower Alkyl-4,6-Pregnadiene- 17a,21-Diol-3,20-Dione 21-Lower Alkanoates (A) 11-substituted-16-lower alkyl-4,6-pregnadiene- 17a,21-diol-3,2 0-dione 21-lower alkanoates (1) To 2.5 g. of l6fl-methyl-4-pregnene-l7a,21-diol- 3,11,20-trione 21-acetate add 5 g. of chloranil in ml. of tert.-butanol-dioxane (4:1). Heat the reaction mixture at reflux temperature for 13 hours under an atmosphere of nitrogen. Evaporate the reaction mixture to a residue and extract the residue with ethyl acetate. Wash the com- 

